Imidazo[4,5-c]quinolines as dna-pk inhibitors

ABSTRACT

The invention relates to compounds of the formulae (I) and (II) in which R1, R2, R3, R4, R5, R8, X and m have the meaning indicated in the claims, and/or physiologically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. The compounds of the formula (I) can be used for the inhibition of serine/threonine protein kinases and for the sensitisation of cancer cells to anticancer agents and/or ionising radiation. The invention also relates to the use of the compounds of the formula (I) in the prophylaxis, therapy or progress control of cancer, tumours, metastases or angiogenesis disorders, in combination with radiotherapy and/or an anticancer agent. The invention furthermore relates to a process for the preparation of the compounds of the formula (I).

The invention relates to compounds of the formulae (I) and (I)

in which R1, R2, R3, R4, R5, R8, X and m have the meaning indicated inthe claims, and/or physiologically acceptable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios. Thecompounds of the formula (I) can be used for the inhibition ofserine/threonine protein kinases and for the sensitisation of cancercells to anticancer agents and/or ionising radiation. The invention alsorelates to the use of the compounds of the formula (I) in theprophylaxis, therapy or progress control of cancer, tumours, metastasesor angiogenesis disorders, in combination with radiotherapy and/or ananticancer agent. The invention furthermore relates to a process for thepreparation of the compounds of the formula (I) by reaction of compoundsof the formula (II) and optionally conversion of a base or acid of thecompounds of the formula (I) into one of its salts.

DNA-dependent protein kinase (DNA-PK) is a serine/threonine proteinkinase which is activated in conjunction with DNA. Biochemical andgenetic data show that DNA-PK consists (a) of a catalytic sub-unit,which is called DNA-PKcs, and (b) two regulatory components (Ku70 andKu80). In functional terms, DNA-PK is a crucial constituent on the onehand of the repair of DNA double-strand breaks (DSBs) and on the otherhand of somatic or V(D)J recombination. In addition, DNA-PK and itscomponents are connected with a multiplicity of further physiologicalprocesses, including modulation of the chromatin structure and telomericmaintenance (Smith & Jackson (1999) Genes and Dev 13: 916; Goytisolo etal. (2001) Mol. Cell. Biol. 21: 3642; Williams et al. (2009) Cancer Res.69: 2100).

Human genetic material in the form of DNA is constantly subjected toattack by reactive oxygen species (ROSs), which are formed principallyas by-products of oxidative metabolism. ROSs are capable of causing DNAdamage in the form of single-strand breaks. Double-strand breaks canarise if prior single-strand breaks occur in close proximity. Inaddition, single- and double-strand breaks may be caused if the DNAreplication fork encounters damaged base patterns. Furthermore,exogenous influences, such as ionising radiation (for example gamma orheavy-ion radiation), and certain anticancer medicaments (for examplebleomycin) are capable of causing DNA double-strand breaks. DSBs mayfurthermore occur as intermediates of somatic recombination, a processwhich is important for the formation of a functional immune system ofall vertebrates. If DNA double-strand breaks are not repaired or arerepaired incorrectly, mutations and/or chromosome aberrations may occur,which may consequently result in cell death. In order to counter thesevere dangers resulting from DNA double-strand breaks, eukaryotic cellshave developed a number of mechanisms to repair them. Higher eukaryotesuse predominantly so-called non-homologous end-joining (NHEJ), in whichthe DNA-dependent protein kinase adopts the key role. Biochemicalinvestigations have shown that DNA-PK is activated most effectively bythe occurrence of DNA-DSBs. Cell lines whose DNA-PK components havemutated and are non-functional prove to be radiation-sensitive (Smithand Jackson, 1999).

Owing to its catalytic domain, which is in the C-terminal catalyticsub-unit (DNA-PKcs), which numbers about 500 amino acids, DNA-PK belongsto the family of phosphatidylinositol-3-kinase-related kinases (PIKKs),where DNA-PK is not a lipid kinase (Hartley et al. (1995) Cell 82: 849;Smith & Jackson (1999) Genes and Dev 13: 916; Lempiäinen & Halazonetis(2009) EMBO J. 28: 3067).

The protein kinase ATM (ataxia-telangiectasia-mutated kinase) likewisebelongs to the PIKK family. It too has central importance in therecognition of DNA damage. Patients suffering from ataxia telangiectasiaexhibit, inter alia, increased sensitivity to ionising radiation. (Lavin& Shiloh (1997) Annu. Rev. Immunol. 15: 177; Rotman & Shiloh (1998) Hum.Mol. Genet. 7: 1555).

It has been described by Izzard et al. (1999) Cancer Res. 59: 2581, thatthe PI3 kinase inhibitor LY294002 inhibits the function of DNA-PK inin-vitro experiments. The IC₅₀ value (concentration at which 50% of theenzyme activity is inhibited) is at a relatively ineffective 1.25 μM(5.0 mM ATP). Although the evidence that the inhibitor LY294002 allowsmammal cells to become more radiation-sensitive, i.e. the cytotoxicityof ionising radiation is increased, in principle implies use in theirradiation therapy of, for example, solid cancer tumours, only a weakincrease in sensitivity to ionising irradiation has been demonstratedfor LY294002 in cellular terms (Rosenzweig et al. (1999) Clin. CancerRes. 3: 1149). KuDOS Pharmaceuticals Ltd. have optimised the leadstructure LY294002 and presented various DNA-PK inhibitors. Theintroduction of a dibenzothiophenyl group led to the inhibitor NU-7441,an ATP-competitive compound having an IC₅₀ value of 20.0 nM (Hardcastleet al. (2005) J. Med. Chem. 48: 7829). KU-0060648 combines inhibitoryproperties with respect to DNA-PK with an improved solubility profile inaqueous medium, but the kinases of the PI3K isoenzyme family arelikewise potently inhibited by KU-0060648. The long-existing need for apotent and selective DNA-PK inhibitor has consequently not beensatisfied to date.

The invention is based on the object of overcoming the disadvantagesindicated in the prior art and of developing effective inhibitors ofDNA-PK which are selective with respect to the related kinases of thePIKK family and are of low molecular size and, in particular, enableeffective application in cancer therapy as radio—andchemosensitisers—with the aim of improving the therapeutic efficacy witha simultaneous reduction in side effects.

The object of the invention is achieved in accordance with theindependent claims. The sub-claims contain preferred embodiments. Inaccordance with the invention, compounds of the formula (I) are provided

in which

-   R1 denotes Y or —(CY₂)_(n)—Ar,-   R2 denotes Y, —(CY₂)_(p)—(C[YR6])_(s)-R7 or -alk-R7,-   R3 denotes Y or CN,-   R4 denotes Y, Hal, —(CY₂)_(p)—COOY or —(CY₂)_(p)—CO—NYY,-   R5 denotes A, Hal, —(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY,    —(CY₂)_(p)—CO—NYY or —(CY₂)_(p)—NY—COY,-   R6 denotes Y, Hal, —(CY₂)_(n)—NYY, —(CY₂)_(n)—NY—COO—(CY₂)_(n)—SiA₃,    —(CY₂)_(n)—COOY, —CO—NYY, —CO—NY—(CY₂)_(n)—OY, —CO—NY—(CY₂)_(n)—NYY    or SO₂A,-   R7 denotes —(CY₂)_(p)—Ar or —(CY₂)_(p)-Het¹,-   X denotes CH₂, O, S or a single bond,-   Y denotes H or A,-   A denotes unbranched or branched alkyl having 1, 2, 3, 4, 5, 6, 7,    8, 9 or 10 C atoms, where 1, 2, 3, 4, 5, 6 or 7 H atoms may be    replaced, independently of one another, by Hal,-   Alk denotes alkenyl having 1, 2, 3, 4, 5 or 6 C atoms, where 1, 2, 3    or 4 H atoms may be replaced, independently of one another, by Hal    and/or OY,-   Ar denotes phenyl which is unsubstituted or mono-, di- or    trisubstituted by Hal, A, CN, —(CY₂)_(p)—OY, —(CY₂)_(p)—NYY,    —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY or —(CY₂)_(p)—NY—COY,-   Het¹ denotes mono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8    or 9 C atoms and 1, 2, 3 or 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted by Hal, A, CN,    —(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY,    —(CY₂)_(p)—NY—COY or —SO₂—Het²,-   Het² denotes a monocyclic saturated heterocycle having 2, 3, 4, 5, 6    or 7 C atoms and 1, 2, 3 or 4 N, O and/or S atoms, which may be    unsubstituted or monosubstituted by A,-   Hal denotes F, Cl, Br or I,-   m denotes 0, 1, 2, 3 or 4, and-   n, p, s, independently of one another, denote 0, 1, 2, 3, 4, 5 or 6,    and/or physiologically acceptable salts, tautomers and/or    stereoisomers thereof, including mixtures thereof in all ratios.

Surprisingly, it has been found that the compounds according to theinvention are provided with inhibiting properties for serine/threonineprotein kinases. The compounds of the formula (I) are designed in such away, through their core structure of2,3-dihydro-1H-imidazo-[4,5-c]quinoline, to which at least one alkoxysubstitution, preferably a methoxy substitution, and an optionallysubstituted phenyl are attached, that potent and selective inhibition ofDNA-PK occurs. The compounds according to the invention thus open upentirely new possibilities with respect to the anticarcinogenic actionof anticancer agents. Remarkably, the compounds of the formula (I) playa therapeutic role as radio- and chemosensitisers in the treatment ofcancer.

To date, it is merely known from WO 1992/07844 that2,4-diaminoquinazoline derivatives are enhancers of chemotherapeuticagents in the treatment of cancer. The derivatives address the multipleresistance of tumour cells as a consequence of overexpression of themdr1 gene, whose gene product of an efflux P glycoprotein pump keeps theintracellular active-compound concentration low. Inhibitors ofphosphatidylinositol 3-kinase are also described generically in WO2009/155527, which have neither the specific structure of formula (I)according to the invention nor the alkoxy substitution. Neither of thetwo prior-art documents discloses physicochemical or pharmacologicaldata. A marketed medicament is equally unknown. By contrast, the presentinvention reveals that specifically compounds of the formula (I) arecapable of the specific inhibition of serine/threonine protein kinases,such as DNA-PK. The compounds according to the invention and saltsthereof consequently have valuable pharmacological properties while atthe same time being well tolerated.

For the purposes of the invention, the compounds of the formula (I) aredefined in such a way that they are also taken to mean pharmaceuticallyusable derivatives, salts, hydrates, solvates, precursors of thecompounds, tautomers and optically active forms (such as, for example,stereoisomers, diastereomers, enantiomers, racemates). Solvates of thecompounds are taken to mean adductions of inert solvent molecules ontothe compounds, which form owing to their mutual attractive force.Solvates are, for example, mono- or dihydrates or alcoholates.Pharmaceutically usable derivatives are taken to mean, for example, thesalts of the compounds according to the invention and so-calledprecursors of the compounds. Precursors are taken to mean, for example,compounds of the formula (I) modified by means of alkyl or acyl groups,sugars or oligopeptides, which are rapidly cleaved in the organism togive the effective compounds according to the invention. These alsoinclude biodegradable polymer derivatives of the compounds according tothe invention, as described, for example, in Int. J. Pharm. 115, 61-67(1995). Any compound which can be converted in vivo into a bioactiveagent, i.e. compounds of the formula (I), is a precursor in the sense ofthis invention. Any biologically active compound which results from thein-vivo metabolisation of a compound according to the invention is ametabolite in the sense of the present invention. The compounds of theformula (I) can have one or more chiral centres and therefore occur invarious stereoisomeric forms. The formula (I) encompasses all theseforms.

The invention also relates to the use of mixtures of the compounds ofthe formula (I), for example mixtures of two diastereomers, for examplein the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. Particularpreference is given here to mixtures of stereoisomeric compounds.

Above and below, the radicals R1, R2, R3, R4, R5, R6, R7, X, Y, A, Alk,Ar, Het¹, Het² and Hal as well as m, n, p and s have the meaningsindicated for the formula (I), unless expressly indicated otherwise. Ifindividual radicals occur a number of times within a compound orradical, the radicals adopt, independently of one another, the meaningsindicated, unless expressly indicated otherwise. For example, theradicals YY in the radical R4, in which they occur a number of times,are identical or different, but are preferably in each case selected,independently of one another, from the meanings indicated above and/orbelow (for example methyl and/or ethyl), unless expressly indicatedotherwise. It likewise goes without saying, for example, that the indexm in the notation (R5)_(m) indicates the frequency of the substitutionby the radical R5, i.e. the phenyl radical may carry up to 4 radicals R5in different positions (but not a concatenation of up to 4 radicals inthe same position), where the respective radicals R5 are selected,identically or differently, but preferably in each case independently ofone another, from the meanings indicated above and/or below. Inaddition, the radicals R5 in the sub-formulae (IA) and (IB), in whichthey occur multiple times, are selected, identically or differently, butpreferably in each case independently of one another, from the meaningsindicated above and/or below (for example A and/or Hal). If R5 occursmultiple times, the radical may alternatively also be denoted by R5′,R5″, R5′″ and R5″″. The terms used here for the definition of thecompounds are generally based on the rules of the IUPAC organisation forchemical compounds and in particular organic compounds. The terms forexplanation of the above-mentioned compounds of the invention alwayshave the following meanings, unless indicated otherwise in thedescription or claims.

The term “unsubstituted” means that a radical, a group or a residuecarries no substituents. The term “substituted” means that a radical, agroup or a residue carries one or more substituents.

“Alkyl” or “A” in the sense of the invention denotes a saturated orunsaturated hydrocarbon radical, which is unbranched (linear), branchedor cyclic and preferably has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms,i.e. C₁₋₁₀-alkanyl. Examples of alkyl radicals are methyl, ethyl,propyl, isopropyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-, 2- or3-methylbutyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-, 2-, 3- or4-methylpentyl, hexyl.

In a preferred embodiment of the invention, “A” is unbranched orbranched alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, where,independently of one another, 1, 2, 3, 4, 5, 6 or 7 H atoms may bereplaced by Hal. “A” is particularly preferably unbranched or branchedalkyl having 1, 2, 3, 4, 5 or 6 C atoms, where 1, 2, 3, 4 or 5 H atomsmay be replaced, independently of one another, by Hal. Very particularpreference is given to C₁₋₄-alkyl, where, independently of one another,1-3 H atoms may be replaced by Hal. A C₁₋₄-alkyl of this type is, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, 1,1,1-trifluoroethyl or bromomethyl, most preferablymethyl, ethyl or trifluoromethyl. It goes without saying that therespective meanings of “A” are independent of one another in theradicals of a formula according to the invention.

The term “Alk” in the sense of the invention denotes unbranched orbranched alkylene, alkenyl or alkynyl having 1, 2, 3, 4, 5 or 6 C atoms,i.e. C₁₋₆-alkylenes, C₂₋₆-alkenyls and C₂₋₆-alkynyls. Alkenyls have atleast one C—C double bond and alkynyls have at least one C—C triplebond. Alkynyls may in addition have at least one C—C double bond.Examples of suitable alkylenes are methylene, ethylene, propylene,butylene, pentylene, hexylene, isopropylene, isobutylene, sec-butylene,1-, 2- or 3-methylbutylene, 1,1-, 1,2- or 2,2-dimethylpropylene,1-ethylpropylene, 1-, 2-, 3- or 4-methylpentylene, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene,1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene, 1,1,2- or1,2,2-trimethylpropylene. Examples of suitable alkenyls are allyl,vinyl, propenyl (—CH₂CH═CH₂; —CH═CH—CH₃; —C(═CH₂)—CH₃), 1-, 2- or3-butenyl, isobutenyl, 2-methyl-1- or 2-butenyl, 3-methyl-1-butenyl,1,3-butadienyl, 2-methyl-1,3-butadienyl, 2,3-dimethyl-1,3-butadienyl,1-, 2-, 3- or 4-pentenyl and hexenyl. Examples of suitable alkynyls areethynyl, propynyl (—CH₂—C≡CH; —C≡C—CH₃), 1-, 2- or 3-butynyl, pentynyl,hexynyl or pent-3-en-1-ynyl, in particular propynyl.

In a preferred embodiment of the invention, “Alk” is alkenyl having 1-6C atoms, i.e. methenyl, ethenyl, propenyl, butenyl, pentenyl or hexenyl,where 1-4 H atoms may be replaced, independently of one another, by Haland/or OY. It is particularly preferred for “Alk” to denote alkenylhaving 1-3 C atoms, where 1-2 H atoms may be replaced by Hal and/or OH.Very particularly preferred examples thereof are methenyl, ethenyl andpropenyl. It goes without saying that the respective meanings of “Alk”are independent of one another in the radicals of a formula according tothe invention.

Skeleton of the formula (I) is any generic or non-generic structure towhich any radical in the sense of the invention, such as, for example.Ar, Het¹ or Het², can be bonded in order to obtain a compound of theformula (I) according to the invention.

The term “aryl”, “carboaryl” or “Ar” in the sense of the inventiondenotes a mono- or polycyclic aromatic hydrocarbon system having 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, preferably 4-10, particularlypreferably 5-8, C atoms, which may optionally be substituted. The term“aryl” includes systems in which the aromatic ring is part of a bi- orpolycyclic saturated, partially unsaturated and/or aromatic system, forexample if the aromatic ring is fused to “aryl”, “heteroaryl” or“heterocyclyl” via any desired ring member of the aryl radical. Thebonding to the basic structure of the formula (I) can take place via anyring member of the aryl group. Examples of suitable “aryl” are phenyl,biphenyl, naphthyl, 1-naphthyl, 2-naphthyl, anthracenyl, indanyl,indenyl, 1,2,3,4-tetrahydronaphthyl, in particular phenyl, o-, m- orp-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- orp-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- orp-trifluoromethylphenyl, o-, m- or p-fluorophenyl, o-, m- orp-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-hydroxyphenyl, o-,m- or p-methoxyphenyl, o-, m- or p-methylsulfonylphenyl, o-, m- orp-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p-methylaminophenyl,o-, m- or p-dimethylaminophenyl, o-, m- or p-aminosulfonylphenyl, o-, m-or p-methylaminosulfonylphenyl, o-, m- or p-aminocarbonylphenyl, o-, m-or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- orp-ethoxycarbonylphenyl, o-, m- or p-acetylphenyl, o-, m- orp-formylphenyl, o-, m- or p-cyanophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, p-iodophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl or 2,5-dimethyl-4-chlorophenyl.

In a preferred embodiment of the invention, “Ar” is phenyl which isunsubstituted or mono, di- or trisubstituted by Hal, A, CN,—(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY or—(CY₂)_(p)—NY—COY. It is particularly preferred for “Ar” to denotephenyl which is unsubstituted or mono- or disubstituted by Hal. It goeswithout saying that the respective meanings of “Ar” are independent ofone another in the radicals of a formula according to the invention.

The term “heteroaryl” in the sense of the invention denotes a 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, preferably 2-9, particularlypreferably 5-, 6- or 7-membered mono- or polycyclic aromatic hydrocarbonradical which contains at least 1, if appropriate also 2, 3, 4 or 5heteroatoms, in particular nitrogen, oxygen and/or sulfur, where theheteroatoms are identical or different. The number of nitrogen atoms ispreferably 0, 1, 2, 3 or 4, and the number of oxygen and sulfur atomsis, independently of one another, 0 or 1. The term “heteroaryl” includessystems in which the aromatic ring is part of a bi- or polycyclicsaturated, partially unsaturated and/or aromatic system, for example ifthe aromatic ring is fused to “aryl”, “heteroaryl” or “heterocyclyl” viaany desired ring member of the heteroaryl radical. The bonding to thebasic structure of the formula (I) can take place via any ring member ofthe heteroaryl group, so long as it appears chemically sensible, wherebonding via the C atoms is preferred.

“Heteroaryl” denotes, irrespective of further substitutions, for example2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -5-yl,1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or-5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or7-indazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, 1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl,2,1,3-benzoxadiazol-5-yl, imidazolyl, triazinyl, phthalazinyl,indolizinyl, pteridinyl, carbazolyl, phenazinyl, phenoxazinyl,phenothiazinyl or acridinyl.

The heterocyclic radicals may also be partially or fully hydrogenated.Unsubstituted heteroaryl may thus, for example, also denote2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or-3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl,tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-,-3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or-6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl,tetrahydro 2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or-5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or-5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro 1-, -2-,-3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,-4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, 2,3-methylenedioxyphenyl,3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl,3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl,2,3-dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxomethylenedioxy)phenyl, oralso 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl,2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

It is preferred for “heteroaryl” in the sense of “Het¹” to denote amono- or bicyclic aromatic heterocycle having 2, 3, 4, 5, 6, 7, 8 or 9 Catoms and 1, 2, 3 or 4 N, O and/or S atoms, which may be unsubstitutedor mono- di- or trisubstituted by Hal, A, CN, —(CY₂)_(p)—OY,—(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY, —(CY₂)_(p)—NY—COY or—SO₂—Het². It is particularly preferred for “Het¹” to denote mono- orbicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8 or 9 C atoms and 1, 2 or3 N and/or S atoms, which may be unsubstituted or mono- or disubstitutedby Hal, A, OY or —SO₂—Het². It goes without saying that the respectivemeanings of “Het¹” are independent of one another in the radicals of aformula according to the invention.

The term “heterocycle” in the sense of the invention denotes a mono- orpolycyclic system having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 ring atoms, preferably 3-14 ring atoms,particularly preferably 3-10 ring atoms, comprising C atoms and 1, 2, 3,4 or 5 heteroatoms, in particular nitrogen, oxygen and/or sulfur, wherethe heteroatoms are identical or different. The cyclic system may besaturated or mono- or polyunsaturated. The term “heteroaryl” includessystems in which the aromatic ring is part of a bi- or polycyclicsaturated, partially unsaturated and/or aromatic system, for example ifthe aromatic ring is fused to “aryl”, “heteroaryl” or “heterocyclyl” viaany desired ring member of the heterocycle. The bonding to the basicstructure of the formula (I) can take place via any ring member of theheterocycle. Examples of suitable heterocycles are pyrrolidinyl,thiapyrrolidinyl, piperidinyl, piperazinyl, oxapiperazinyl,oxapiperidinyl, oxadiazolyl, tetrahydrofuryl, imidazolidinyl,thiazolidinyl, tetrahydropyranyl, morpholinyl, tetrahydrothiophenyl,dihydropyranyl.

In an embodiment of the invention, “Het²” is a monocyclic saturatedheterocycle having 2, 3, 4, 5, 6 or 7 C atoms and 1, 2, 3 or 4 N, Oand/or S atoms, which may be unsubstituted or monosubstituted by A. Itis preferred for “Het²” to denote a monocyclic saturated heterocyclehaving 3, 4 or 5 C atoms and 1 or 2 N and/or O atoms.

The term “halogen”, “halogen atom”, “halogen substituent” or “Hal” inthe sense of the invention denotes one or more atoms of fluorine (F),bromine (Br), chlorine (Cl) or iodine (I). The terms “dihalogen”,“trihalogen” and “perhalogen” relate to two, three or four substituents,where each substituent can be selected, independently of one another,from the group of F, Cl, Br or I. “Halogen” preferably means F, Cl orBr. F and Cl are particularly preferred, in particular if the halogensare substituted on an alkyl (haloalkyl) or alkoxy group (for example CF₃and CF₃O).

The radical R1 preferably denotes H or A, particularly preferably A.

The radical R2 preferably denotes H, A, —(CY₂)_(p)—C(YR6)-R7, R7,-Alk-Ar or -Alk-Het¹, particularly preferably H, A, —CH(R6)-R7, Het¹ or-Alk-Het¹.

The radical R3 preferably denotes H or CN, particularly preferably CN.

The radical R4 preferably denotes H or A, particularly preferably A.

The radical R5 preferably denotes Y or Hal, particularly preferably H orHal, very particularly preferably Hal.

The radical R6 preferably denotes Y, —(CY₂)_(n)—NYY, —CO—NYY or—CO—NY—(CY₂)_(n)—OY, particularly preferably H, —CH₂—NH₂, —CO—NH₂ or—CO—NH—(CH₂)_(n)—OA, very particularly preferably H.

The radical R7 preferably denotes Ar or Het¹.

The radical X preferably denotes O or a single bond.

The index m preferably denotes 0, 1 or 2, particularly preferably 1 or2.

The index n preferably denotes 0, 1, 2 or 3, particularly preferably 1or 2.

The index p preferably denotes 0, 1, 2 or 3, particularly preferably 0.

The index s preferably denotes 0, 1, 2 or 3, particularly preferably 0or 1.

Accordingly, the invention relates to the compounds of the formula (I)in which at least one of the said radicals has one of the meaningsindicated above. Radicals which are not denoted in greater detail in thecontext of an embodiment of the formula (I), part-formula thereof or anyresidue thereon are intended to have the meaning indicated for theformula (I), as disclosed herein, in order to achieve the object of theinvention. This means that the said radicals may adopt all meaningsassigned to them, as described above or below, including any preferredembodiments, without being restricted thereto and independently of theiroccurrence in another particular context. It goes without saying, inparticular, that each embodiment of a certain radical can be combinedwith each embodiment of one or more other radicals.

In a preferred embodiment of the present invention,imidazolonylquinoline derivatives of the sub-formula (IA) are provided

in which

-   R2 denotes Y or —(CY₂)_(p)—C(YR6)-R7,-   R5 denotes Y or Hal,-   R6 denotes Y, —(CY₂)_(n)—NYY, —CO—NYY or —CO—NY—(CY₂)_(n)—OY,-   R7 denotes Ar or Het¹,-   Y denotes H or A,-   A denotes unbranched or branched alkyl having 1, 2, 3 or 4 C atoms,    where 1, 2 or 3 H atoms may be replaced, independently of one    another, by Hal,-   Ar denotes phenyl which is unsubstituted or mono- or disubstituted    by Hal,-   Het¹ denotes mono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8    or 9 C atoms and 1, 2 or 3 N and/or S atoms, which may be    unsubstituted or mono- or disubstituted by Hal, A, OY or —SO₂—Het²,-   Het² denotes a monocyclic saturated heterocycle having 3, 4 or 5 C    atoms and 1 or 2 N and/or O atoms,-   Hal denotes F, Cl, Br or I, and-   n, p, independently of one another, denote 0, 1, 2 or 3,    and/or physiologically acceptable salts, tautomers and/or    stereoisomers thereof, including mixtures thereof in all ratios.

In another preferred embodiment of the present invention,imidazolonylquinoline derivatives of the sub-formula (IB) are provided

in which

-   R2 denotes R7, -alk-Ar or -alk-Het¹,-   R5 denotes Y or Hal,-   R7 denotes —(CY₂)_(p)—Ar or —(CY₂)_(p)-Het¹,-   Y denotes H or A,-   A denotes unbranched or branched alkyl having 1, 2, 3 or 4 C atoms,    where 1, 2 or 3 H atoms may be replaced, independently of one    another, by Hal,-   Alk denotes alkenyl having 1, 2 or 3 C atoms, where 1 or 2 H atoms    may be replaced by Hal and/or OH,-   Ar denotes phenyl which is unsubstituted or mono- or disubstituted    by Hal,-   Het¹ denotes mono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8    or 9 C atoms and 1, 2 or 3 N and/or S atoms, which may be    unsubstituted or mono- or disubstituted by Hal, A, OY or —SO₂—Het²,-   Het² denotes a monocyclic saturated heterocycle having 3, 4 or 5 C    atoms and 1 or 2 N and/or O atoms, Hal denotes F, Cl, Br or I, and-   p, independently of one another, denotes 0, 1, 2 or 3,    and/or physiologically acceptable salts, tautomers and/or    stereoisomers thereof, including mixtures thereof in all ratios.

In a particularly preferred embodiment of the present invention,imidazolonylquinoline derivatives of the sub-formula (IB-1) are provided

in which

-   R2 denotes R7, -alk-Ar or -alk-Het¹,-   R5 denotes Hal,-   R7 denotes Ar or Het¹,-   A denotes unbranched or branched alkyl having 1, 2, 3 or 4 C atoms,    where 1, 2 or 3 H atoms may be replaced, independently of one    another, by Hal,-   Alk denotes alkenyl having 1 or 2 C atoms,-   Ar denotes phenyl which is unsubstituted or monosubstituted by Hal,-   Het¹ denotes mono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8    or 9 C atoms and 1, 2 or 3 N and/or S atoms, which may be    unsubstituted or mono- or disubstituted by Hal or A or, and-   Hal denotes F, Cl, Br or I,    and/or physiologically acceptable salts, tautomers and/or    stereoisomers thereof, including mixtures thereof in all ratios.

Very particular preference is given to compounds of the formulae (I),(IA), (IB) and (IB-1) which are compiled in Table 1.

TABLE 1 Very particularly preferred compounds of the formulae (I), (IA),(IB) and (IB-1) and/or physiologically acceptable salts, tautomersand/or stereoisomers thereof, including mixtures thereof in all ratios 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

The compounds of the formula (I) and also the starting materials fortheir preparation are prepared by methods known per se, as are describedin the literature (for example in standard works, such as Houben-Weyl,Methoden der organischen Chemie [Methods of Organic Chemistry],Georg-Thieme-Verlag, Stuttgart) and/or are known person skilled in theart, and under reaction conditions which are known and suitable for thesaid reactions. Use can also be made here of variants known per se whichare not mentioned here in greater detail.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between −15° C. and150° C., normally between 10° C. and 100° C., particularly preferablybetween 20° C. and 70° C.

The reaction is carried out in an inert solvent and generally in thepresence of an acid-binding agent, preferably an organic base, such asDIPEA, triethylamine, dimethylaniline, pyridine, quinoline, piperidineor diethanolamine. The addition of an alkali-metal or alkaline-earthmetal hydroxide, carbonate or bicarbonate or another salt of a weak acidof the alkali or alkaline-earth metals, preferably of potassium, sodium,calcium or caesium, may also be favourable. Suitable bases are metaloxides, such as, for example, aluminium oxide, alkali-metal hydroxides(including potassium hydroxide, sodium hydroxide and lithium hydroxide),alkaline-earth metal hydroxides (for example barium hydroxide andcalcium hydroxide) and alkali-metal alkoxides (for example potassiumethoxide and sodium propoxide).

Suitable inert solvents are, inter alia, hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents. Particular preference is given to glycol ethers,such as ethylene glycol monomethyl ether, THF, dichloromethane and/orDMF.

The process and the subsequent work-up of the reaction mixture canbasically be carried out as a batch reaction or in a continuous reactionprocedure. The continuous reaction procedure comprises, for example,reaction in a continuous stirred-kettle reactor, a stirred-kettlecascade, a loop or cross-flow reactor, a flow tube or in a microreactor.The reaction mixtures are optionally worked up, as needed, by filtrationvia solid phases, chromatography, separation between immiscible phases(for example extraction), adsorption onto solid supports, removal ofsolvents and/or azeotropic mixtures by distillation, selectivedistillation, sublimation, crystallisation, co-crystallisation or bynanofiltration on membranes.

The compounds of the formula (I) can preferably be obtained by reactinga compound of the formula (II). The present invention thus also relatesto a process for the preparation of compounds of the formula (I),part-formulae thereof and/or physiologically acceptable salts, tautomersand/or stereoisomers thereof, including mixtures thereof in all ratios,having the following steps:

-   (a) reaction of a compound of the formula (II)

-   -   in which    -   R1 denotes A,    -   R2 denotes A or —(CH₂)_(p)—(CH₂)_(s)—Ar,    -   R3 denotes CN,    -   R5 denotes Hal,    -   R8 denotes NH₂,    -   A denotes unbranched or branched alkyl having 1, 2, 3 or 4 C        atoms, where 1, 2 or 3 H atoms may be replaced, independently of        one another, by Hal,    -   Ar denotes phenyl which is unsubstituted or mono- or        disubstituted by Hal,    -   Hal denotes F, Cl, Br or I, and    -   m, p, s, independently of one another, denote 0, 1 or 2,    -   preferably in which    -   R8 denotes NO₂ or NYY, particularly preferably NYY, and    -   R1, R2, R3, R5, R6, R7, Y, A, Alk, Ar, Het1, Het² and Hal as        well as m, n, p and s have the meaning indicated above in        formula (I),    -   with a carboxylic acid halide and with an organic base,        preferably Hünig's base, in a solvent,    -   to give compounds of the sub-formula (IC)

-   -   in which R1, R2, R3, R5 and m have the meaning indicated above        in formula (II), and optionally

-   (b′) reaction of the compounds of the sub-formula (IC) with a    compound Hal-R4, in which R4 and Hal have the meaning indicated    above,    -   to give compounds of the sub-formula (ID)

-   -   in which R1, R2, R3, R5 and m have the the meaning indicated        above in formula (II), and R4 has the meaning indicated above,

-   (b″) conversion of R1, —O—R2, R3, R4 and/or R5 of the compounds of    the sub-formula (ID) and/or addition of at least one R5 having the    meaning indicated above to the phenyl ring of the compounds of the    sub-formula (ID) to give compounds of the formula (I)

-   -   in which R1, R2, R3, R4, R5, X and m have the meaning indicated        above,    -   and/or

-   (b′″) conversion of a base or acid of the compounds of the    formula (I) or sub-formulae (IC) or (ID) into one of its    physiologically acceptable salts.

For the purposes of the invention, it goes without saying here that aradical can adopt all meanings given previously in the description forthe corresponding radical by reference to “the meaning indicated above”without more detailed specification thereof.

The invention also relates to intermediate compounds of the formula (II)

in whichR8 denotes NO₂ or NYY, andR1, R2, R3, R5, Y and m have the meaning indicated above,and/or salts, tautomers and/or stereoisomers thereof, including mixturesthereof in all ratios.

In a preferred embodiment of the present invention, intermediatecompounds of the formula (II) are provided in which

-   R1 denotes A,-   R2 denotes A or —(CH₂)_(p)—(CH₂)_(s)—Ar,-   R3 denotes CN,-   R5 denotes Hal,-   R8 denotes NH₂,-   A denotes unbranched or branched alkyl having 1, 2, 3 or 4 C atoms,    where 1, 2 or 3 H atoms may be replaced, independently of one    another, by Hal,-   Ar denotes phenyl which is unsubstituted or mono- or disubstituted    by Hal,-   Hal denotes F, Cl, Br or I, and-   m, p, s, independently of one another, denote 0, 1 or 2,    and/or salts, tautomers and/or stereoisomers thereof, including    mixtures thereof in all ratios.

The invention also relates to a process for the preparation ofintermediate compounds of the formula (II) and/or salts, tautomersand/or stereoisomers thereof, including mixtures thereof in all ratios,having the following steps:

-   (a) reaction of a compound of the formula (III)

-   -   in which R1, R2, R8 and Hal have the meaning indicated above,    -   with a compound of the formula (IV)

-   -   in which R3, R5 and m have the meaning indicated above,    -   to give compounds of the formula (II)

-   -   in which R1, R2, R3, R5, R8 and m have the meaning indicated        above.    -   and optionally

-   (b) conversion of a base or acid of the compounds of the    formula (II) into one of its salts.

The starting compounds are generally known. If they are novel, they canbe prepared by methods known per se. The compounds of the formulae (III)and (IV) can be prepared by known methods. If desired, the startingmaterials can be formed in situ, so that they are not isolated from thereaction mixture, but instead are immediately converted further into thecompounds according to the invention. It is likewise possible to carryout the reaction stepwise.

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula(I) and part-formulae thereof are for the most part prepared byconventional methods. If the compounds contain a carboxyl group, one ofits suitable salts can be formed by reacting the compound with asuitable base to give the corresponding base-addition salt. Such basesare, for example, alkali-metal hydroxides (for example potassiumhydroxide, sodium hydroxide and lithium hydroxide), alkaline-earth metalhydroxides (for example barium hydroxide and calcium hydroxide),alkali-metal alkoxides (for example potassium ethoxide and sodiumpropoxide) and various organic bases, such as piperidine, diethanolamineand N-methylglutamine. A base of the formulae (I) and (II) andpart-formulae thereof can be converted into the associated acid-additionsalt using an acid, for example by reaction of equivalent amounts of thebase and the acid in an inert solvent, such as, for example, ethanol,with subsequent evaporation. Suitable acids for this reaction are, inparticular, those which give physiologically acceptable salts, such as,for example, hydrogen halides (for example hydrogen chloride, hydrogenbromide or hydrogen iodide), other mineral acids and corresponding saltsthereof (for example sulfate, nitrate or phosphate and the like), alkyl-and monoarylsulfonates (for example ethanesulfonate, toluenesulfonateand benzenesulfonate) and other organic acids and corresponding saltsthereof (for example acetate, trifluoroacetate, tartrate, maleate,succinate, citrate, benzoate, salicylate, ascorbate and the like. Saltswith physiologically unacceptable acids, for example picrates, can beused for the isolation and/or purification of the compounds of theformula (I).

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active compound which comprises a compound of the formula (I) inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active compound compared withthe free form of the active compound. The pharmaceutically acceptablesalt form of the active compound can also provide this active compoundfor the first time with a desired pharmacokinetic property and can evenhave a positive influence on the pharmacodynamics of this activecompound with respect to its therapeutic efficacy in the body. Compoundsaccording to the invention may be chiral owing to their molecularstructure and may accordingly occur in various enantiomeric forms. Theymay therefore be in racemic or optically active form. Since thepharmaceutical efficacy of the racemates or stereoisomers of thecompounds of the formula (I) may differ, it may be desirable to use theenantiomers. In these cases, the end product, or even the intermediate,may be separated into enantiomeric compounds by chemical or physicalmeasures known to the person skilled in the art or already employed assuch in the synthesis.

Surprisingly, it has been found that the compounds according to theinvention cause specific inhibition of serine/threonine protein kinases.The invention therefore furthermore relates to the use of compounds ofthe formula (I) or part-formulae thereof and/or physiologicallyacceptable salts, tautomers and/or stereoisomers thereof, includingmixtures thereof in all ratios, for the inhibition of serine/threonineprotein kinases, preferably PIKK and/or ATM, particularly preferablyDNA-PK. The term “inhibition” relates to any reduction in the activitywhich is based on the action of the specific compounds according to theinvention in that the latter are capable of interacting with the targetmolecule in such a way that recognition, binding and blocking is madepossible. The compounds are distinguished by high affinity to at leastone serine/threonine protein kinases, ensuring reliable binding andpreferably complete blocking of the kinase activity. The compounds areparticularly preferably monospecific in order to guarantee exclusive anddirect recognition of the selected kinase. The term “recognition”relates here to any type of interaction between the compound and thesaid target molecules, in particular covalent or non-covalent bonds,such as, for example, a covalent bond, hydrophobic/hydrophilicinteractions, van der Waals forces, ion attraction, hydrogen bonds,ligand/receptor interactions, base pairs of nucleotides or interactionsbetween epitope and antibody binding site.

The compounds according to the invention exhibit an advantageousbiological activity which can be demonstrated in the tests describedherein, such as, for example, enzymebased assays. Measurement of thekinase activity is a technique which is well known to the person skilledin the art. Generic test systems for the determination of the kinaseactivity using substrates, for example histone (Alessi et al. (1996)FEBS Lett. 399(3): 333) or the basic myelin protein, are described inthe literature (Campos-González & Glenney (1992) JBC 267: 14535).Various assay systems are available for the identification of kinaseinhibitors. In the scintillation proximity assay (Sorg et al. (2002) JBiomolecular Screening 7: 11) and the flashplate assay, the radioactivephosphorylation of a protein or peptide as substrate are measured usingATP. In the presence of an inhibitory compound, a decreased radioactivesignal, or none at all, is detectable. Furthermore, homogeneoustime-resolved fluorescence resonance energy transfer (HTR-FRET) andfluorescence polarisation (FP) technologies are useful as assay methods(Sills et al. (2002) J Biomolecular Screening 191). Othernon-radioactive ELISA methods use specific phospho-antibodies(phospho-ABs). The phospho-AB binds only the phosphorylated substrate.This binding can be detected by chemiluminescence using a secondperoxidase-conjugated anti-sheep antibody.

The above-mentioned use of the compounds can take place in in-vitro orin-vivo models. The susceptibility of a particular cell to treatmentwith the compounds according to the invention can be determined bytesting in vitro. Typically, a culture of the cell is incubated with acompound according to the invention at various concentrations for aperiod of time which is sufficient to enable the active agents to inducecell death or to inhibit cell proliferation, cell vitality or migration,usually between about one hour and one week. For testing in vitro,cultivated cells from a biopsy sample can be used. The amount of cellsremaining after the treatment is then determined. The use in vitro takesplace, in particular, on samples of mammal species which are sufferingfrom cancer, tumours, metastases, angiogenesis disorders, retroviraldiseases, immune diseases and/or pathogenic ageing processes. The hostor patient can belong to any mammal species, for example a primatespecies, in particular humans, but also rodents (including mice, ratsand hamsters), rabbits, horses, cows, dogs, cats, etc. Animal models areof interest for experimental investigations, providing a model for thetreatment of a human disease.

The testing of a plurality of specific compounds enables the selectionof the active compound which appears the most suitable for the treatmentof the patient. The in-vivo dose of the selected compound isadvantageously matched to the susceptibility of the kinase and/orseverity of the disease of the patient taking into account the in-vitrodata, as a result of which the therapeutic efficacy is noticeablyincreased. The dose varies depending on the specific compound used, thespecific disease, the patient status, etc. A therapeutic dose istypically sufficient considerably to reduce the undesired cellpopulation in the target tissue, while the viability of the patient ismaintained. The following teaching of the invention and embodimentsthereof relating to the use of compounds of the formula (I) for thepreparation of a medicament for the prophylaxis, therapy and/or progresscontrol is valid and can be applied without restrictions to the use ofthe compounds for the inhibition of the kinase activity, if it appearsappropriate.

The treatment is generally continued until a considerable reduction hasoccurred, for example at least about 50% reduction of the cell load, andcan be continued until essentially no more undesired cells are detectedin the body. In tests of this type, the compounds according to theinvention exhibit and cause an inhibiting effect, which is usuallydocumented by IC₅₀ values in a suitable range, preferably in themicromolar range and more preferably in the nanomolar range. The kinaseis inhibited, in particular, to the extent of 50% if the concentrationof the compounds is less than 1 μM, preferably equal to or less than 0.5μM, particularly preferably less than 0.1 μM. This concentration iscalled the IC₅₀ value.

The invention also relates to a medicament comprising at least onecompound of the formula (I) or part-formulae thereof and/orphysiologically acceptable salts, tautomers and/or stereoisomersthereof, including mixtures thereof in all ratios. The invention alsorelates to a pharmaceutical composition comprising, as active compound,an effective amount of at least one compound of the formula (I) orpart-formulae thereof and/or physiologically acceptable salts, tautomersand/or stereoisomers thereof, including mixtures thereof in all ratios,together with pharmaceutically tolerated assistants.

A “medicament”, “drug” and a “pharmaceutical composition” or“pharmaceutical formulation” here is any composition which can beemployed in the prophylaxis, therapy, progress control or aftertreatmentof patients who, at least temporarily, exhibit a pathogenic modificationof the overall condition or the condition of individual parts of thepatient organism, preferably as a consequence of cancer, tumours,metastases, angiogenesis disorders, retroviral diseases, immune diseasesand/or accelerated ageing processes, particularly preferably as aconsequence of cancer, tumours, metastases and/or angiogenesisdisorders.

In order to increase the protective or therapeutic action of thecompounds according to the invention, pharmaceutically toleratedadjuvants can be added. For the purposes of the invention, any substancewhich facilitates, enhances or modifies an effect with the compounds inaccordance with the invention is an “adjuvant”. Known adjuvants are, forexample, aluminium compounds, such as, for example, aluminium hydroxideor aluminium phosphate, saponins, such as, for example, QS 21, muramyldipeptide or muramyl tripeptide, proteins, such as, for example,gamma-interferon or TNF, MF 59, phosphatdibylcholine, squalene orpolyols. The co-application of egg albumin in complete Freund's adjuvantcan likewise cause increased cell-mediated immunity and thus support theaction of neutralising antibodies formed. Furthermore, DNA, which has animmunostimulatory property, or which encodes a protein with an adjuvanteffect, such as, for example, a cytokine, can be applied in parallel orin a construct.

The introduction of the pharmaceutical composition into a cell ororganism can be carried out in accordance with the invention in anymanner which enables the kinases to be brought into contact with thecompounds present in the composition, as a consequence of which aresponse is induced. The pharmaceutical composition of the presentinvention can be administered orally, transdermally, transmucosally,transurethrally, vaginally, rectally, pulmonarily, enterally and/orparenterally. The type of administration selected depends on theindication, the dose to be administered, individual-specific parameters,etc. In particular, the various types of administration facilitatesite-specific therapy, which minimises side effects and reduces theactive-compound dose. Very particularly preferred injections areintradermal, subcutaneous, intramuscular or intravenous injection. Theadministration can be carried out, for example, with the aid ofso-called vaccination guns or by means of syringes. It is also possibleto prepare the substance as an aerosol, which is inhaled by theorganism, preferably a human patient.

The administration forms of the pharmaceutical composition are preparedcorresponding to the desired type of administration in a suitable dosageand in a manner known per se using the conventional solid or liquidvehicles and/or diluents and the assistants usually employed. Thus,pharmaceutically acceptable excipients known to the person skilled inthe art can basically form part of the pharmaceutical compositionaccording to the invention, where the amount of excipient material whichis combined with the active compound in order to prepare a single dosevaries depending on the individual to be treated and the type ofadministration. These pharmaceutically tolerated additives includesalts, buffers, fillers, stabilisers, complexing agents, antioxidants,solvents, binders, lubricants, tablet coatings, flavours, dyes,preservatives, adjusters and the like. Examples of excipients of thistype are water, vegetable oils, benzyl alcohols, alkylene glycol,polyethylene glycol, glycerol triacetate, gelatine, carbohydrates, suchas, for example, lactose or starch, magnesium stearate, talc andVaseline.

The pharmaceutical formulation can be in the form of a tablet, filmtablet, dragee, lozenge, capsule, pill, powder, granules, syrup, juice,drops, solution, dispersion, suspension, suppository, emulsion, implant,cream, gel, ointment, paste, lotion, serum, oil, spray, aerosol,adhesive, plaster or bandage. Oral administration forms which areprepared are preferably tablets, film tablets, dragees, lozenges,capsules, pills, powders, granules, syrups, juices, drops, solutions,dispersions or suspensions—including as depot form. Furthermore,parenteral medicament forms, such as, for example, suppositories,suspensions, emulsions, implants or solutions, should be considered,preferably oily or aqueous solutions. For topical application, themedicament active compound is formulated in a conventional manner withat least one pharmaceutically acceptable vehicle, such as, for example,microcrystalline cellulose, and optionally further assistants, such as,for example, moisturisers, to give solid formulations which can beapplied to the skin, such as, for example, creams, gels, ointments,pastes, powders or emulsions, or to give liquid formulations which canbe applied to the skin, such as, for example, solutions, suspensions,lotions, sera, oils, sprays or aerosols. The pharmaceutical compositionis preferably in the form of an injection solution. For the preparationof the injection solution, aqueous media, such as, for example,distilled water or physiological salt solutions, can be used, where thelatter include acidic and basic addition salts. The pharmaceuticalcomposition may also be in the form of a solid composition, for examplein the lyophilised state, and can then be prepared before use byaddition of a dissolving agent, such as, for example, distilled water.The person skilled in the art is familiar with the basic principles ofthe preparation of lyophilisates.

The concentration of the active compound in the formulation can be 0.1to 100 percent by weight. It is crucial that the pharmaceuticalcomposition comprises, as active compound, an effective amount of thecompound together with the pharmaceutically tolerated assistants. Theterms “effective amount” or “effective dose” are used interchangeablyherein and denote an amount of the pharmaceutical active compound whichhas a prophylactically or therapeutically relevant action on a diseaseor pathological change in cell, tissue, organ or mammal. A “prophylacticaction” prevents the outbreak of a disease or even infection with apathogen after ingress of individual representatives in such a way thatsubsequent spread thereof is greatly reduced or they are even completelydeactivated. A “prophylactic action” also includes an increase in normalphysiological function. Prophylaxis is advisable, in particular, if anindividual has predispositions for the onset of the above-mentioneddiseases, such as, for example, a family history, a gene defect or arecently survived disease. A “therapeutically relevant action” frees inpart or full from one, more than one or all disease symptoms or resultsin the partial or complete reversal of one, more than one or allphysiological or biochemical parameters which are associated with orcausally involved in the disease or pathological change into the normalstate. Progress control is also taken to be a type of therapeutictreatment if the compounds are administered at certain time intervals,for example in order completely to eliminate the symptoms of a disease.The respective dose or dose range for the administration of thecompounds according to the invention is sufficiently large to achievethe desired prophylactic or therapeutic effect of induction of abiological or medical response. In general, the dose will vary with theage, constitution and gender of the patient, and the severity of thedisease will be taken into account. It goes without saying that thespecific dose, frequency and duration of administration are, inaddition, dependent on a multiplicity of factors, such as, for example,the targeting and binding ability of the compounds, feeding habits ofthe individual to be treated, type of administration, excretion rate andcombination with other drugs. The individual dose can be adjusted bothwith respect to the primary disease and also with respect to theoccurrence of any complications. The precise dose can be established bya person skilled in the art using known means and methods. This teachingof the invention is valid and can be applied without restrictions to thepharmaceutical composition comprising the compounds of the formula (I),if it appears appropriate.

In an embodiment of the invention, the compounds are administered in adose of 0.01 mg to 1 g per dosage unit, preferably between 1 to 700 mg,particularly preferably 5 to 100 mg. The daily dose is in particularbetween 0.02 and 100 mg/kg of body weight.

In order to support the medical effect, the pharmaceutical compositionmay, in an embodiment of the invention, also comprise one or morefurther active compounds, where simultaneous or successiveadministration is conceivable. The therapeutic effect of thepharmaceutical composition according to the invention can consist, forexample, in certain anticancer agents having a better action through theinhibition of DNA-PK as a desired side effect or in the number of sideeffects of these medicaments being reduced by the reduction in the dose.

In a preferred embodiment of the invention, the pharmaceuticalcomposition according to the invention is combined with an anticanceragent. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer, tumours, metastasesand/or angiogenesis disorders for the purpose of treatment of thecancer. The anticancer agent is particularly preferably selected fromthe group comprising cytokines, chemokines, pro-apoptotic agents,interferons, radioactive compounds, oestrogen receptor modulators,androgen receptor modulators, retinoid receptor modulators, cytotoxicagents, cytostatic agents, prenyl-protein transferase inhibitors andangiogenesis inhibitors or combinations thereof. It is preferred for theanticancer agent to modify, in particular reduce, nucleic acid and/orprotein metabolism, cell division, DNA replication, purine, pyrimidineand/or amino acid biosynthesis, gene expression, mRNA processing,protein synthesis, apoptosis or combinations thereof.

The invention can also be practised as a kit which comprises thecompounds according to the invention. The kit consists of separate packsof (a) an effective amount of a compound of the formula (I) and/orphysiologically acceptable salts, tautomers and/or stereoisomersthereof, including mixtures thereof in all ratios, and (b) an effectiveamount of a further active compound. The kit comprises suitablecontainers, such as, for example, boxes or cartons, individual bottles,bags or ampoules. The kit may, for example, comprise separate ampoules,each containing an effective amount of a compound of the formula (I)and/or pharmaceutically usable salts, tautomers and/or stereoisomersthereof, including mixtures thereof in all ratios, and an effectiveamount of a further medicament active compound in dissolved orlyophilised form. The kit of the invention may also contain an articlewhich contains written instructions or points the user towards writteninstructions which explain the handling of the compounds of theinvention.

In accordance with the invention, the compounds of the formula (I) orpart-formulae thereof and/or physiologically acceptable salts, tautomersand/or stereoisomers thereof, including mixtures thereof in all ratios,are used for the prophylaxis, therapy and/or progress control ofdiseases which are caused, promoted and/or spread by the activity ofserine/threonine protein kinases. The present invention therefore alsorelates to the use of compounds of the formula (I) or part-formulaethereof and/or physiologically acceptable salts, tautomers and/orstereoisomers thereof, including mixtures thereof in all ratios, for thepreparation of a medicament for the prophylaxis, therapy and/or progresscontrol of diseases which are caused, promoted and/or spread by theactivity of serine/threonine protein kinases. In accordance with theinvention, compounds of the formula (I) or part-formulae thereof and/orphysiologically acceptable salts, tautomers and/or stereoisomersthereof, including mixtures thereof in all ratios, are suitable for usein the prophylaxis, therapy and/or progress control of diseases whichare caused, promoted and/or spread by activity of serine/threonineprotein kinases. For the identification of a corresponding signallingpathway and in order to detect interactions between various signallingpathways, suitable models or model systems have been developed, forexample cell culture models (Khwaja et al. (1997) EMBO 16: 2783) andmodels of transgenic animals (White et al. (2001) Oncogene 20: 7064). Inorder to determine certain stages in the signalling cascade, interactingcompounds can be used in order to modulate the signal (Stephens et al.(2000) Biochemical J 351: 95). In addition, the compounds according tothe invention can also be used as reagents for testing kinase-dependentsignalling pathways in animals and/or cell culture models or in theclinical diseases mentioned in this application. As discussed herein,these signalling pathways are relevant for various diseases.Accordingly, the compounds according to the invention are useful in theprophylaxis, therapy and/or progress control of diseases which aredependent on signalling pathways with participation by serine/threonineprotein kinases.

In accordance with the invention, the compounds of the formula (I) orpart-formulae thereof and/or physiologically acceptable salts, tautomersand/or stereoisomers thereof, including mixtures thereof in all ratios,are suitable for use in the prophylaxis, therapy and/or progress controlof cancer, tumours, metastases, angiogenesis disorders, retroviraldiseases and/or immune diseases, in particular cancer, tumours,metastases and/or angiogenesis disorders. In accordance with theinvention, the compounds of the formula (I) or part-formulae thereofand/or physiologically acceptable salts, tautomers and/or stereoisomersthereof, including mixtures thereof in all ratios, are also suitable foruse in the slowing of ageing processes, where the slowing takes placewith reference to the comparison of the life span of the treated host orcells, cell cultures, tissues or organs thereof with correspondingpositive or negative controls and/or statistics. It goes without sayingthat the host of the pharmaceutical compounds is also included in thescope of protection of the present invention.

The tumour is, in particular, selected from the group of diseases ofsquamous epithelium, bladder, stomach, kidneys, head, neck, oesophagus,cervix, thyroid, intestine, liver, brain, prostate, urogenital tract,lymphatic system, larynx, lung, skin, blood and immune system, and/orthe cancer is selected from the group of monocytic leukaemia, lungadenocarcinoma, small-cell lung carcinoma, pancreatic cancer,glioblastoma, bowel carcinoma, breast carcinoma, acute myeloidleukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia, chroniclymphatic leukaemia, Hodgkin's lymphoma and non-Hodgkin's lymphoma.

A further embodiment of the present invention relates to the compoundsaccording to the invention in combination with radiotherapy and/or withat least one further active compound, preferably in combination withradiotherapy and/or an anticancer agent. Industrial irradiation methodswhich are used clinically preferably include photon irradiation(classical, electromagnetic X-ray/gamma radiation), proton irradiation,heavy-ion irradiation (ionised carbon) and neutron irradiation, withoutbeing restricted thereto. These radiotherapies and other suitableirradiation therapies in the sense of the invention are known to theperson skilled in the art, such as, for example, from Herrmann et al.(2006) Klinische Strahlenbiologie [Clinical Radiation Biology], ElsevierMunich, 4th Edition, 67-68; Bhide & Nutting (2010) BMC Medicine 8: 25;Choi & Hung (2010) Current Urology Reports 11(3): 172. As the mostfrequent application, photon irradiation has been refined technically bythe IMRT (intensity-modulated radiotherapy) method and by imagingmethods (three-dimensional conformal radiotherapy) in irradiationplanning and performance for the most precise focusing possible. Thecompounds according to the invention achieve synergistic effects inexisting cancer chemotherapies and irradiations and/or restore theefficacy of existing cancer chemotherapies and irradiations. Thesynergistic action of the inhibition of VEGF in combination withradiotherapy is described in the prior art (WO 00/61186). The furthermedicament active compounds are particularly preferably chemotherapeuticagents which inhibit angiogenesis and thus inhibit the growth and spreadof tumour cells. Examples thereof are VEGF receptor inhibitors,comprising ribozymes and antisense which are directed at VEGF receptors,and angiostatin and endostatin. Further examples of antineoplasticagents which can be used in combination with the compounds according tothe invention generally include alkylating agents, antimetabolites,epidophyllotoxin, an antineoplastic enzyme, a topoisomerase inhibitor,procarbazine, mitoxantrone or platinum coordination complexes. Inanother embodiment, the anticancer agent is particularly preferablyselected from the group of oestrogen receptor modulator, androgenreceptor modulator, retinoid receptor modulator, cytotoxic agent,cytostatic agent, prenyl-protein transferase inhibitor and angiogenesisinhibitor. In addition, the previous teaching of the invention andembodiments thereof relating to pharmaceutical composition is valid andcan be applied without restrictions to the second medical indication, ifit appears appropriate. A very particularly preferred embodimentencompasses the compounds according to the invention in combination withradiotherapy and/or a cytostatic agent.

Still a further embodiment of the invention relates to the use of atleast one compound of the formula (I) and/or physiologically acceptablesalts, tautomers and/or stereoisomers thereof, including mixturesthereof in all ratios, for the sensitisation of cancer cells to ananticancer agent and/or ionising radiation, with the proviso that thesensitisation does not take place in vivo on the human or animal body.The sensitisation preferably takes place ex vivo or in vitro byadministering the compounds to cells, cell cultures, tissues or organswhich comprise serine/threonine protein kinases. The ex-vivo use isused, in particular, in the case of animal cells which originate from ananimal organism which is affected by a disease which is selected fromthe group of cancer, tumours, metastases and/or angiogenesis disorders.The cells treated ex vivo can either continue to be kept in culture forsubsequent investigations or transferred into an animal, which can bethe host animal or another animal. The ex-vivo sensitisation accordingto the invention is particularly advantageous for testing the specificaction of the compounds, so that the in-vivo dose can be pre-adjustedcorrespondingly with evaluation of these ex-vivo data. As a resultthereof, the therapeutic effect is increased significantly.Alternatively, the invention is also designed for use in-vivo andrelates to at least one compound of the formula (I) and/orphysiologically acceptable salts, tautomers and/or stereoisomersthereof, including mixtures thereof in all ratios, for use for thesensitisation of cancer cells to an anticancer agent and/or ionisingradiation.

The invention furthermore teaches a method for the prophylaxis, therapyand/or progress control of cancer, tumours, metastases, angiogenesisdisorders, retroviral diseases, immune diseases and/or ageing processesin which an effective amount of at least one compound according to theinvention and/or physiologically acceptable salts, tautomers and/orstereoisomers thereof, including mixtures thereof in all ratios, isadministered to a subject to be treated. Preferred subjects in the senseof the invention are humans or animals, particularly preferably humans.It is known to the person skilled in the art here that he can administerthe compounds according to the invention, which can of course also beused as the pharmaceutical composition according to the invention, invarious doses to an organism, in particular a human patient. Theeffective amount and the type of administration can be determined by theperson skilled in the art by routine experiments. The previous teachingof the invention and embodiments thereof are valid and can be appliedwithout restrictions to the treatment method, if it appears appropriate.

All said and further constituents or components are familiar to theperson skilled in the art and can experience a specific embodiment forthe teaching according to the invention in routine experiments. Alldocuments cited in the description are hereby intended to beincorporated in their entirety into the disclosure of the presentinvention as reference.

As part of the invention presented here, novel2,3-dihydro-1H-imidazol[4,5-c]quinoline compounds of the formula (I)were provided for the first time. The compounds according to theinvention control serine/threonine protein kinases, in particularDNA-PK, affinitively and/or selectively. The compounds from formula (I)and derivatives thereof are distinguished by high specificity andstability, low preparation costs and easy handling. These propertiesform the basis for a reproducible mode of action, including the absenceof cross-reactivities, and reliable and safe interaction with thecorresponding target structures. The invention also includes the use ofthe present 2,3-dihydro-1H-imidazol[4,5-c]quinoline derivatives for theinhibition, regulation and/or modulation of the signalling cascade ofserine/threonine protein kinases, in particular DNA-PK, and thus offersnovel tools for research and/or diagnostics.

Medicaments and pharmaceutical compositions which comprise the saidcompounds and the use of these compounds for the treatment ofkinase-promoted disorders are, in addition, a highly promising approachfor a broad spectrum of therapies, enabling direct and immediatealleviation of symptoms to be achieved in humans and animals. This isparticularly advantageous for effective combating of severe diseases,such as cancer, either as monotherapy or in combination with otherantineoplastic therapies. The key participation by DNA-PK in DNA repairprocesses and the evidence that the DNA-PK inhibitors allows mammalcells to become more radiation-sensitive enable therapeutic use ofDNA-PK or DNA-PK/ATM or ATM-specific inhibitors as part of the treatmentof, for example, solid cancer tumours by radiotherapy and/orchemotherapy aimed at DNA-DSBs. The compounds of the formula (I), salts,isomers, tautomers, enantiomers, diastereomers, racemates, derivatives,prodrugs and/or metabolites thereof are effective not only in the caseof the said clinical disease pictures, but likewise in the diagnosis andtherapy of all diseases in connection with the DNA-PK signallingcascade, in particular with respect to the inhibition of cellproliferation and migration. In addition, the inhibitors according tothe invention can be used in the treatment of retroviral diseases bysuppression of retroviral integration (R. Daniel (1999) Science 284:644). Finally, the inhibitors according to the invention can be employedas immunomodulators and modulators of telomeric maintenance. Thelow-molecular-weight inhibitors are used individually and/or incombination with other treatment measures, such as, for example,surgical interventions, immunotherapy, radiotherapy and/or chemotherapy.The latter relate to targeted therapy with any desired NME (i.e. NCEand/or NBE) as monotherapy and/or on-target/off-target combinationtherapy.

Owing to their surprisingly strong and/or selective inhibition ofenzymes which regulate cellular processes via the repair of dsDNA, thecompounds of the invention can be administered in advantageously lowdose, while they achieve a similar or even superior biological efficacycompared with the less-potent or less-selective inhibitors of the priorart. The reduced dose is also accompanied by reduced or no medical sideeffects. In addition, the highly selective inhibition by the compoundsaccording to the invention is also reflected by a reduction in undesiredside effects, which is independent of the dose.

It goes without saying that this invention is not restricted to thespecific compounds, pharmaceutical compositions, uses and methods asdescribed herein, since such things can be varied. It furthermore goeswithout saying that the terminology used here serves exclusively thepurpose of description of particular embodiments and is not intended torestrict the scope of protection of the invention. As used here in thespecification, including the appended claims, word forms in thesingular, such as, for example, “a” or “the”, include the equivalent inthe plural, so long as the context does not specifically indicateotherwise. For example, the reference to “a compound” includes a singlecompound or a plurality of compounds, which may in turn be identical ordifferent, or the reference to “a method” includes equivalent steps andmethods which are known to the person skilled in the art. The inventionis explained in greater detail below with reference to non-limitingexamples of specific embodiments. The examples should, in particular, beinterpreted as not being restricted to the feature combinationsspecifically illustrated, but instead the illustrative features can inturn be freely combined so long as the object of the invention isachieved.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate, evaporated and purified by chromatographyon silica gel and/or by crystallisation. Rf values on silica gel;eluent: ethyl acetate/methanol 9:1.

NMR (1H) was carried out with the following parameters.

Instruments: Bruker Avance DRX 500, Bruker Avance 400, Bruker DPX 300Reference: TMS

TD (time domain=number of data points or digital resolution): 65536

Solvent: DMSO d6

NS (number of scans): 32SF (spectrometer frequency=transmission frequency): 500 MHzTE (temperature): 303 KHPLC-MS was carried out with the following parameters.Instrument: Agilent Technologies 1200 seriesMethods: ESI1 ROD.M and POLAR.M (3.8 min., solvent gradient)

Column: ChromolithSpeedROD RP18e50-4.6

Solvent: acetonitrile+0.05% of HCOOH/deionised water+0.04% of HCOOHDetection wavelength: 220 nmMS type: API-ES

EXAMPLE 1 Synthesis of3-fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile

6-Benzyloxy-7-methoxy-3-nitro-1H-quinolin-4-one (9.10 g, 27.89 mmol, seeActa Pharmacologica Sinica 2008, 29(12), 1529-1538) was suspended in dryN,N-dimethylformamide (70 ml). Phosphoryl chloride (2.82 ml, 30.68 mmol)was subsequently added, and the mixture was heated at 100° C. for 30min. After cooling, the reaction mixture was added to ice-water (500 ml)with stirring and stirred for a further 30 min. The precipitate formedwas filtered off with suction, washed with water and dried in vacuo,giving 6-benzyloxy-4-chloro-7-methoxy-3-nitroquinoline (9.57 g, 27.76mmol) as solid. MS: 345.1 (M+H⁺), TLC (HPTLC): R_(f)=0.44(cyclohexane/ethyl acetate 2:1, parts by volume).

6-Benzyloxy-4-chloro-7-methoxy-3-nitroquinoline (6.75 g, 19.58 mmol) and4-amino-3-fluorobenzonitrile (2.46 g, 18.1 mmol) were dissolved inglacial acetic acid (106 ml) and stirred at 50° C. for 18 h overnight.The suspension obtained was subsequently added to water (11) and stirredfor a further 30 min. The precipitate formed was filtered off withsuction, rinsed with water and dried in vacuo, giving4-(6-benzyloxy-7-methoxy-3-nitro-quinolin-4-ylamino)-3-fluorobenzonitrile(6.69 g, 15.06 mmol) as solid. MS: 445.1 (M+H⁺), TLC (HPTLC): R_(f)=0.31(cyclohexane/ethyl acetate 2:1, parts by volume).

4-(6-Benzyloxy-7-methoxy-3-nitroquinolin-4-ylamino)-3-fluorobenzonitrile(6.50 g, 14.62 mmol) and tin(II) chloride dihydrate (14.70 g, 65.15mmol) were dissolved in ethanol (780 ml). The reaction solution wassubsequently stirred at 70° C. for 30 min. When the reaction wascomplete (TLC, LC-MS), water (2 l) and ethyl acetate (1.5 l) was added,and the mixture was stirred vigorously for a further 30 min. Thesuspension obtained was filtered through kieselguhr. The aqueous phasewas extracted again with ethyl acetate (11), and the combined organicphases were washed with water (500 ml). After the organic phase had beendried over Na₂SO₄, the solid material was filtered off with suction, andthe filtrate was evaporated to dryness in vacuo, giving4-(3-amino-6-benzyloxy-7-methoxyquinolin-4-ylamino)-3-fluorobenzonitrile(3.40 g, 8.2 mmol) as solid. MS: 415.1 (M+H⁺), TLC (HPTLC): R_(f)=0.47(ethyl acetate).

4-(3-Amino-6-benzyloxy-7-methoxyquinolin-4-ylamino)-3-fluorobenzonitrile(2.99 g, 7.2 mmol) was dissolved in dichloromethane (69 ml) togetherwith Hünig's base (iPr₂EtN, 1.43 ml). The solution obtained wassubsequently added dropwise with ice-bath cooling to a mixture oftrichloromethyl chloroformate (diphosgene, 938 μl, 7.72 mmol) anddichloromethane (42 ml). When the addition was complete, the mixture wasstirred at room temperature for a further 30 min. Saturated Na₂CO₃ (30ml) and water (170 ml) were subsequently added. After stirring for afurther 30 min, the mixture was extracted twice with ethyl acetate (225ml each time). The combined organic phases were washed once with water(150 ml), dried over Na₂SO₄, filtered and evaporated to dryness invacuo. The residue was chromatographed over flash silica gel (solventgradient ethyl acetate/0-17% by vol. of ethanol), giving4-(8-benzyloxy-7-methoxy-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)-3-fluorobenzonitrile (1.87 g, 4.3 mmol) as solid.MS: 441.1 (M+H⁺), TLC (HPTLC): R_(f)=0.44 (ethyl acetate/ethanol 8:1,parts by volume).

Benzyloxy-7-methoxy-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)-3-fluorobenzonitrile(1.73 g, 3.93 mmol) was dissolved in N,N-dimethylformamide (40 ml).Iodomethane (294 μl, 4.7 mmol) and K₂CO₃ (1.09 g, 7.86 mmol) weresubsequently added. The reaction mixture was stirred at room temperaturefor 18 h overnight. The suspension was then added to water (600 ml) andstirred for a further 30 min. The precipitate was filtered off, rinsedwith water and chromatographed over flash silica gel (solvent gradientdichloromethane/0-15% by vol. of methanol), giving4-(8-benzyloxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)-3-fluorobenzonitrile(1.64 g, 3.61 mmol) as solid. MS: 455.1 (M+H⁺), TLC (HPTLC): R_(f)=0.34(ethyl acetate/ethanol 8:1, parts by volume). ¹H NMR (400 MHz, DMSO)δ=8.78 (s, 1H), 8.23-8.16 (m, 1H), 8.00-7.86 (m, 2H), 7.46 (s, 1H),7.40-7.29 (m, 3H), 7.18-7.10 (m, 2H), 6.27 (s, 1H), 4.85-4.73 (m, 2H),3.92 (s, 3H), 3.54 (s, 3H).

A boron tribromide solution in dichloromethane (1.0 M, 14.5 ml, 14.5mmol) was slowly added dropwise with ice-bath cooling in a dry nitrogenatmosphere to a solution of4-(8-benzyloxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)-3-fluorobenzonitrile(1.45 g, 3.19 mmol) in trifluoroacetic acid (29 ml). When the additionwas complete, the mixture were subsequently stirred for a further 30min. When the reaction was complete (HPLC-MS check), the reactionmixture was carefully added to water (700 ml) and extracted twice withethyl acetate (290 ml each time). The combined organic phases werewashed with water (100 ml) and semi-saturated NaHCO₃ solution (150 ml),subsequently dried using Na₂SO₄ and filtered with suction. The filtratewas evaporated in vacuo, and the residue was chromatographed over flashsilica gel (solvent gradient ethyl acetate/0-33% by vol. of ethanol),giving3-fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile(1.10 g, 3.03 mmol), as solid. MS: 365.1 (M+H⁺), TLC (HPTLC): R_(f)=0.46(ethyl acetate/ethanol 2:1, parts by volume). ¹H NMR (400 MHz, DMSO)b=9.93 (s, 1H), 8.73 (s, 1H), 8.32 (dd, J=9.7, 1.5, 1H), 8.09-7.93 (m,2H), 7.39 (s, 1H), 6.32 (s, 1H), 3.89 (s, 3H), 3.54 (s, 3H).

Compounds which were prepared in accordance with Example 1 are shown inTable 2 below.

TABLE 2 Compounds of the formulae (I) and (IA) IC₅₀ DNA-PK No.Structural formula Name Analysis [μM] 1

4-(7,8-Dimethoxy-2-oxo-2,3- dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile MS: 347.1 (M + H⁺), TLC (HPTLC): R_(f) = 0.48 (ethylacetate/ethanol 8:1, parts by volume) <0.1 2

4-(7,8-Dimethoxy-3-methyl-2- oxo-2,3-dihydroimidazo-[4,5-c]quinolin-1-yl)- benzonitrile MS: 361.1 (M + H⁺), TLC (HPTLC):R_(f) = 0.46 (ethyl acetate/ethanol 8:1, parts by volume) <0.1 3

4-(8-Hydroxy-7-methoxy-3- methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)- benzonitrile MS: 347.1 (M + H⁺), TLC(HPTLC): R_(f) = 0.32 (ethyl acetate/ethanol 2:1, parts by volume) <0.14

3-Fluoro-4-(8-hydroxy-7- methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin- 1-yl)benzonitrile MS: 365.1 (M + H⁺), TLC(HPTLC): R_(f) = 0.46 (ethyl acetate/ethanol 2:1, parts by volume) <0.15

3,5-Difluoro-4-(8-hydroxy-7- methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin- 1-yl)benzonitrile MS: 383.1 (M + H⁺), TLC(HPTLC): R_(f) = 0.35 (ethyl acetate/ethanol 5:1, parts by volume) >0.16

4-(8-Benzyloxy-7-methoxy-2- oxo-2,3-dihydroimidazo-[4,5-c]quinolin-1-yl)- benzonitrile MS: 423.1 (M + H⁺), TLC (HPTLC):R_(f) = 0.51 (ethyl acetate/ethanol 8:1, parts by volume) <0.1 7

4-(8-Benzyloxy-7-methoxy-3- methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)- benzonitrile MS: 437.1 (M + H⁺), TLC(HPTLC): R_(f) = 0.44 (ethyl acetate/ethanol 8:1, parts by volume) <0.18

4-(8-Benzyloxy-7-methoxy-2- oxo-2,3-dihydroimidazo-[4,5-c]quinolin-1-yl)-3- fluorobenzonitrile MS: 441.1 (M + H⁺), TLC(HPTLC): R_(f) = 0.52 (ethyl acetate/ethanol 5:1, parts by volume) <0.19

4-(8-Benzyloxy-7-methoxy-3- methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3- fluorobenzonitrile MS: 455.1 (M + H⁺),TLC (HPTLC): R_(f) = 0.42 (ethyl acetate/ethanol 5:1, parts by volume)<0.1 10

4-(8-Benzyloxy-7-methoxy-2- oxo-2,3-dihydroimidazo-[4,5-c]quinolin-1-yl)-3,5- difluorobenzonitrile MS: 459.1 (M + H⁺), TLC(HPTLC): R_(f) = 0.42 (ethyl acetate/ethanol 5:1, parts by volume) <0.111

4-(8-Benzyloxy-7-methoxy-3- methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)- 3,5-difluorobenzonitrile MS: 473.1 (M +H⁺), TLC (HPTLC): R_(f) = 0.41 (ethyl acetate/ethanol 5:1, parts byvolume) <0.1 12

Methyl 8-benzyloxy-1-(4- cyano-2-fluorophenyl)-7- methoxy-2-oxo-1,2-dihydroimidazo[4,5-c]- quinoline-3-carboxylate MS: 499.2 (M + H⁺), TLC(HPTLC): R_(f) = 0.70 (ethyl acetate/ethanol 5:1, parts by volume) <0.1

EXAMPLE 2 Synthesis of3-fluoro-4-(7-methoxy-3-methyl-2-oxo-8-(thiophen-3-ylmethoxy)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile

3-Fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile(80 mg, 220 μmol) was dissolved in N,N-dimethylformamide (4.0 ml) undera dry argon atmosphere. Potassium carbonate (85 mg, 618 μmol) and3-chloromethylthiophene (112 mg, 845 μmol; prepared from3-thiophenemethanol using SOCl₂ in CH₂Cl₂) were subsequently added. Thereaction mixture was stirred at 50° C. for 18 h overnight. When thereaction was complete, the mixture was poured into water (60 ml),stirred for 30 min and extracted twice with ethyl acetate (75 ml eachtime). The combined organic phases were washed with water (25 ml),subsequently dried over Na₂SO₄, filtered with suction and evaporated invacuo. The residue chromatographed over flash silica gel (solventgradient ethyl acetate/0-17% by vol. of ethanol), giving3-fluoro-4-(7-methoxy-3-methyl-2-oxo-8-(thiophen-3-ylmethoxy)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile(64 mg, 139 μmol), as solid. MS: 461.1 (M+H⁺), TLC (HPTLC): R_(f)=0.33(ethyl acetate/ethanol 5:1, parts by volume).

Compounds which were prepared in accordance with the synthetic procedurefrom Example 2 are shown in Table 3 below.

TABLE 3 Compounds of the formulae (I) and (IA) IC₅₀ DNA-PK No.Structural formula Name Analysis [μM] 13

3-Fluoro-4-(7-methoxy-3-methyl- 2-oxo-8-(thiophen-3-ylmethoxy)-2,3-dihydroimidazo[4,5-c]- quinolin-1-yl)benzonitrile MS: 461.1 (M +H⁺), TLC (HPTLC): R_(f) = 0.33 (ethyl acetate/ethanol 5:1, parts byvolume) <0.1 14

3-Fluoro-4-(7-methoxy-3-methyl- 2-oxo-8-(thiophen-2-ylmethoxy)-2,3-dihydroimidazo[4,5-c]- quinolin-1-yl)benzonitrile MS: 461.1 (M +H⁺), TLC (HPTLC): R_(f) = 0.61 (ethyl acetate/ethanol 2:1, parts byvolume) <0.1 15

2-[1-(4-Cyano-2-fluorophenyl)-7- methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]- quinolin-8-yloxy]-2-(4-fluoro-phenyl)acetamide MS: 516.1 (M + H⁺), TLC (HPTLC): R_(f) = 0.41-0.50(ethyl acetate/ ethanol 2:1, parts by volume) <0.1 16

2-[1-(4-Cyano-2-fluorophenyl)-7- methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]- quinolin-8-yloxy]-2-(4-fluoro-phenyl)-N-(2-methoxyethyl)- acetamide MS: 574.2 (M + H⁺), TLC (HPTLC):R_(f) = 0.29-0.37 (ethyl acetate/ ethanol 2:1, parts by volume) 0.1-0.517

3-Fluoro-4-[8-(4-fluoro- benzyloxy)-7-methoxy-3-methyl-2-oxo-2,3-dihydro- imidazo[4,5-c]quinolin-1-yl]- benzonitrile MS: 473.1(M + H⁺), TLC (HPTLC): R_(f) = 0.47 (ethyl acetate/ethanol 2:1, parts byvolume) <0.1 18

2-[1-(4-Cyano-2-fluorophenyl)-7- methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]- quinolin-8-yloxy]-2-phenyl- acetamide MS:498.1 (M + H⁺), TLC (HPTLC): R_(f) = 0.27-0.38 (ethyl acetate/ ethanol5:1, parts by volume) <0.1 19

3-Fluoro-4-{7-methoxy-3-methyl- 8-[3-(morpholine-4-sulfonyl)-thiophen-2-ylmethoxy]-2-oxo- 2,3-dihydro-1H-imidazo[4,5-c]-quinolin-1-yl}benzonitrile MS: 610.1 (M + H⁺), TLC (HPTLC): R_(f) = 0.53(ethyl acetate/ethanol 2:1, parts by volume) 0.1-0.5 20

3-Fluoro-4-[7-methoxy-3-methyl- 2-oxo-8-(pyridin-4-ylmethoxy)-2,3-dihydroimidazo[4,5-c]- quinolin-1-yl]benzonitrile MS: 456.1 (M +H⁺), TLC (HPTLC): R_(f) = 0.36 (ethyl acetate/ethanol 2:1, parts byvolume) <0.1 21

4-[8-(2-Bromobenzyloxy)-7- methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1- yl]-3-fluorobenzonitrile MS:533.0/535.0 (M + H⁺) (monobromo isotope distribu- tion approx. 100:98),TLC (HPTLC): R_(f) = 0.49 (ethyl acetate/ethanol 2:1, parts by volume)<0.1 22

4-[8-(2-Bromo-4- fluorobenzyloxy)-7-methoxy-3- methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3- fluorobenzonitrile MS: 551.0/553.0 (M +H⁺) (monobromo isotope distribu- tion approx. 100:98), TLC (HPTLC):R_(f) = 0.49 (ethyl acetate/ethanol 2:1, parts by volume) <0.1 23

4-[8-(2-Chloro-4- fluorobenzyloxy)-7-methoxy-3-methyl-2-oxo-2,3-dihydro- imidazo[4,5-c]quinolin-1-yl]-3-fluorobenzonitrile MS: 507.0/509.0 (M + H⁺), (monochloro isotopedistribu- tion approx. 100:32) TLC (HPTLC): R_(f) = 0.51 (ethylacetate/ethanol 2:1, parts by volume) <0.1 24

4-[8-(3-Chloro-4- fluorobenzyloxy)-7-methoxy-3-methyl-2-oxo-2,3-dihydro- imidazo[4,5-c]quinolin-1-yl]-3-fluorobenzonitrile MS: 507.0/509.0 (M + H⁺), (monochloro isotopedistribu- tion approx. 100:32) TLC (HPTLC): R_(f) = 0.53 (ethylacetate/ethanol 5:1, parts by volume) <0.1 25

2-[1-(4-Cyano-2,6-difluoro- phenyl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo- [4,5-c]quinolin-8-yloxy]-2-(4-fluorophenyl)acetamide MS: 534.1 (M + H⁺), TLC (HPTLC): R_(f) = 0.44(ethyl acetate/ethanol 5:1, parts by volume) <0.1 26

3,5-Difluoro-4-(7-methoxy-3- methyl-2-oxo-8-(thiophen-3-ylmethoxy)-2,3-dihydroimidazo- [4,5-c]quinolin-1-yl)benzonitrile MS:479.1 (M + H⁺), TLC (HPTLC): R_(f) = 0.50 (ethyl acetate/ethanol 5:1,parts by volume) <0.1 27

3,5-Difluoro-4-[8-(4-fluoro- benzyloxy)-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo- [4,5-c]quinolin-1-yl]benzonitrile MS: 491.1(M + H⁺), TLC (HPTLC): R_(f) = 0.50 (ethyl acetate/ethanol 5:1, parts byvolume) <0.1 28

3,5-Difluoro-4-(7-methoxy-3- methyl-2-oxo-8-(thiophen-2-ylmethoxy)-2,3-dihydroimidazo- [4,5-c]quinolin-1-yl)benzonitrile MS:479.1 (M + H⁺), TLC (HPTLC): R_(f) = 0.72 (ethyl acetate/ethanol 5:1,parts by volume) <0.1 29

4-(7-Methoxy-3-methyl-2-oxo- 8-(thiophen-3-ylmethoxy)-2,3-dihydroimidazo[4,5-c]quinolin- 1-yl)benzonitrile MS: 443.1 (M + H⁺), TLC(HPTLC): R_(f) = 0.50 (ethyl acetate/ethanol 8:1, parts by volume) <0.1

EXAMPLE 3a Synthesis of3-fluoro-4-[7-methoxy-3-methyl-2-oxo-8-(thiazol-5-ylmethoxy)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile

For the preparation, see also synthesis of 2-trimethylsilanylethyl{2-[1-(4-cyano-2-fluorophenyl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yloxy]-2-thiophen-2-ylethyl}carbamateunder Example 3b:3-fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile(63 mg, 173 μmol), triphenylphosphine (polymer-bound) (294 mg, 1.12mmol), thiazol-5-ylmethanol (62 mg, 540 μmol), diisopropylazodicarboxylate (166 μl, 845 μmol) in tetrahydrofuran (7 ml) werereacted, giving3-fluoro-4-[7-methoxy-3-methyl-2-oxo-8-(thiazol-5-ylmethoxy)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]benzonitrile(15 mg, 32.5 μmol) as solid. MS: 462.0 (M+H⁺), TLC (HPTLC): R_(f)=0.44(ethyl acetate/ethanol 2:1, parts by volume).

EXAMPLE 3b Synthesis of4-[8-(2-amino-1-thiophen-2-ylethoxy)-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]-3-fluorobenzonitrile

3-Fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile(350 mg, 961 μmol) and diphenyl-2-pyridylphosphine (1.46 g, 5.39 mmol)were dissolved in tetrahydrofuran (105 ml). 2-Trimethylsilanylethyl(2-hydroxy-2-thiophen-2-ylethyl)carbamate (787 mg, 2.74 mmol) anddiisopropyl azodicarboxylate (788 μl, 4.01 mmol) were subsequentlyadded. The reaction mixture was stirred at room temperature for 15 min.When the reaction was complete (HPLC-MS), it was added to ethyl acetate(50 ml) and saturated sodium chloride solution (50 ml) and extracted.The aqueous phase was extracted with further ethyl acetate (25 ml). Thecombined organic phases were washed with water (25 ml), dried overNa₂SO₄ and filtered. The filtrate was evaporated to dryness in vacuo,and the residue was chromatographed over flash silica gel (solventgradient ethyl acetate/0-7% by vol. of ethanol), giving2-trimethylsilanylethyl{2-[1-(4-cyano-2-fluorophenyl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yloxy]-2-thiophen-2-ylethyl}carbamate(253 mg, 399 μmol) as solid. MS: 634.2 (M+H⁺), TLC (HPTLC): R_(f)=0.34(ethyl acetate/ethanol 8:1, parts by volume).

2-Trimethylsilanylethyl{2-[1-(4-cyano-2-fluorophenyl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yloxy]-2-thiophen-2-ylethyl}carbamate (239mg, 377 μmol) was dissolved in dimethyl sulfoxide (40 ml) under a drynitrogen atmosphere. CsF (1.15 g, 7.60 mmol) was subsequently added, andthe reaction mixture was stirred at room temperature for 18 h overnight.For work-up, the mixture was decanted off into water (300 ml), andsaturated NaHCO₃ solution (25 ml) was added. The aqueous phase wasextracted three times with ethyl acetate (100 ml each time). Thecombined organic phases were washed with saturated sodium chloridesolution (50 ml), dried over Na₂SO₄ and filtered. After evaporation ofthe filtrate, the residue was purified by preparative HPLC (water/1-50%by vol. of acetonitrile in 15 min, flow rate 50 ml/min), giving4-[8-(2-amino-1-thiophen-2-ylethoxy)-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]-3-fluorobenzonitrile(83 mg, 170 μmol) as lyophilisate after freeze-drying of the productfractions. MS: 490.1 (M+H⁺), TLC (HPTLC): R_(f)=0.50 (methanol/iPr₂EtN99:1, parts by volume).

Compounds which were prepared in accordance with the syntheticprocedures from Example 3a and 3b are shown in Table 4 below.

TABLE 4 Compounds of the formulae (I) and (IA) IC₅₀ DNA-PK No.Structural formula Name Analysis [μM] 30

3-Fluoro-4-[7-methoxy-3- methyl-2-oxo-8-(thiazol- 5-ylmethoxy)-2,3-dihydroimidazo[4,5-c]- quinolin-1-yl)benzonitrile MS: 462.0 (M + H⁺),TLC (HPTLC): R_(f) = 0.44 (ethyl acetate/ethanol 2:1, parts by volume)<0.1 31

4-[8-(2-Amino-1- thiophen-2-ylethoxy)-7- methoxy-3-methyl-2-oxo-2,3-dihydroimidazo- [4,5-c]quinolin-1-yl]-3- fluorobenzonitrile MS:490.1 (M + H⁺), TLC (HPTLC): R_(f) = 0.50 (methanol/Hunig's base 99:1,parts by volume) 0.1-0.5 32

4-{8-[2-Amino-1-(4- fluorophenyl)ethoxy]-7- methoxy-3-methyl-2-oxo-2,3-dihydro- imidazo[4,5-c]quinolin- 1-yl}-3- fluorobenzonitrile MS:502.1 (M + H⁺), TLC (HPTLC): R_(f) = 0.28 (methanol/Hunig's base 99:1,parts by volume) 0.5-1.0

EXAMPLE 4a Synthesis of3-fluoro-4-[7-methoxy-3-methyl-2-oxo-8-(2-thiophen-3-ylethyl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]benzonitrile

3-Fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile(162 mg, 444 μmol), N-phenyltrifluoromethanesulfonimide (317 mg, 887μmol) and Hünig's base (300 μl, 1.76 mmol) were dissolved inN,N-dimethylformamide (15 ml). The mixture was subsequently stirred atroom temperature for 30 min. For work-up, the mixture was poured intowater (50 ml) and stirred for a further 30 min. The precipitate formedwas then filtered off with suction and rinsed with water. The filtercake was dried at room temperature overnight in a high vacuum andchromatographed over flash silica gel (solvent gradient ethylacetate/0-25% by vol. of ethanol), giving[1-(4-cyano-2-fluorophenyl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]trifluoromethanesulfonate (185 mg, 373 μmol) as solid. MS: 497.0 (M+H⁺),TLC (HPTLC): R_(f)=0.49 (ethyl acetate/ethanol 2:1, parts by volume).

1-(4-Cyano-2-fluorophenyl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yltrifluoromethanesulfonate (119 mg, 240 μmol),4,4,5,5-tetramethyl-2-[(E)-2-thiophen-3-ylvinyl]-1,3,2-dioxaborolane(142 mg, 602 μmol), tripotassium phosphate (107 mg, 504 μmol) andtrans-bis(tricyclohexylphosphine)palladium(II) dichloride (18 mg, 24μmol) were dissolved in oxygen-free N,N-dimethylformamide (5 ml). Themixture was subsequently heated at 130° C. for 45 min (microwave). Thereaction mixture was then filtered with suction, the filtrate wasdiluted with water and stirred at room temperature for 30 min.

The precipitate formed was filtered off with suction and rinsed withwater. The residue was chromatographed on flash silica gel (solventgradient ethyl acetate/0-25% by vol. of ethanol), giving3-fluoro-4-{7-methoxy-3-methyl-2-oxo-8-[(E)-2-thiophen-3-ylvinyl]-2,3-dihydroimidazo[4,5-c]quinolin-1-yl}benzonitrile(90 mg, 181 μmol) as solid. MS: 457.1 (M+H⁺), TLC (HPTLC): R_(f)=0.47(ethyl acetate/ethanol 2:1, parts by volume).

3-Fluoro-4-{7-methoxy-3-methyl-2-oxo-8-[(E)-2-thiophen-3-ylvinyl]-2,3-dihydroimidazo[4,5-c]quinolin-1-yl}benzonitrile(63 mg, 138 μmol) were dissolved in ethanol (50 ml) and treated with H₂on Pd/C (10%). The reaction mixture was filtered through kieselguhr withsuction, rinsed, and the filtrate was evaporated to dryness. Forpurification, the mixture was chromatographed (preparative HPLC, solventgradient water/1-40% by vol. of acetonitrile in 10 min, flow rate 50ml/min), giving, after freeze-drying,3-fluoro-4-[7-methoxy-3-methyl-2-oxo-8-(2-thiophen-3-ylethyl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]benzonitrile(7.4 mg, 16 μmol) as lyophilisate. MS: 458.8 (M+H⁺), TLC (HPTLC):R_(f)=0.56 (ethyl acetate/ethanol 2:1, parts by volume).

EXAMPLE 4b Synthesis of3-fluoro-4-(7-methoxy-3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile

1-(4-Cyano-2-fluorophenyl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yltrifluoromethanesulfonate (79 mg, 159 μmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (325 mg, 1.27mmol), tripotassium phosphate (70 mg, 319 μmol) andtrans-bis(tricyclohexylphosphine)palladium(II) dichloride (35 mg, 48μmol) were dissolved in oxygen-free N,N-dimethylformamide (4.7 ml). Thereaction mixture was subsequently heated at 130° C. for 90 min(microwave). The mixture was then decanted off into water (50 ml) andstirred for a further 30 min. The precipitate formed was filtered offwith suction and rinsed with water. The filter cake was subsequentlysuspended in a little cold dimethyl sulfoxide, filtered off and rinsedwith 2-propanol, giving3-fluoro-4-(7-methoxy-3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile(41 mg, 86 μmol) as colourless solid after drying in a high vacuum. MS:476.1 (M+H⁺), TLC (HPTLC): R_(f)=0.24 (ethyl acetate/ethanol 5:1, partsby volume).

¹H NMR (500 MHz, CDCl₃) (=8.91 (d, J=2.1, 1H), 8.78 (s, 1H), 8.13 (d,J=8.4, 1H), 8.06 (d, J=1.6, 1H), 7.82 (d, J=8.1, 1H), 7.80-7.73 (m, 2H),7.69 (t, J=8.6, 2H), 7.62 (dd, J=14.4, 6.9, 2H), 7.16 (s, 1H), 3.98 (s,3H), 3.69 (s, 3H).

Compounds which were prepared in accordance with the syntheticprocedures from Example 4a and 4b are shown in Table 5 below.

TABLE 5 Compounds of the formulae (I) and (IB) IC₅₀ DNA-PK No.Structural formula Name Analysis [μM] 33

3-Fluoro-4-(7-methoxy-3-methyl- 2-oxo-8-pyridin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)- benzonitrile MS: 426.1 (M + H⁺), TLC(HPTLC): R_(f) = 0.21 (ethyl acetate/ethanol 5:1, parts by volume) <0.134

3-Fluoro-4-[7-methoxy-8-(6- methoxypyridin-3-yl)-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]- quinolin-1-yl)benzonitrile MS: 456.1 (M +H⁺), TLC (HPTLC): R_(f) = 0.29 (ethyl acetate/ethanol 10:1, parts byvolume) <0.1 35

3-Fluoro-4-(7-methoxy-3-methyl- 2-oxo-8-quinolin-3-yl-2,3-dihydroimidazo[4,5-c]quinolin-1- yl)benzonitrile MS: 476.1 (M + H⁺), TLC(HPTLC): R_(f) = 0.24 (ethyl acetate/ethanol 5:1, parts by volume) <0.136

3-Fluoro-4-[7-methoxy-3-methyl- 8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3-dihydroimidazo[4,5-c]- quinolin-1-yl]benzonitrile MS: 429.1 (M +H⁺), TLC (HPTLC): R_(f) = 0.29 (ethyl acetate/ethanol 5:1, parts byvolume) <0.1 37

3-Fluoro-4-[7-methoxy-3-methyl- 2-oxo-8-(1H-pyrazol-4-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1- yl)benzonitrile Ms: 415.1 (M + H⁺), TLC(HPTLC): R_(f) = 0.38 (ethyl acetate/ethanol 5:1, parts by volume) <0.138

3-Fluoro-4-[7-methoxy-3-methyl- 8-(2-methyl-2H-pyrazol-3-yl)-2-oxo-2,3-dihydroimidazo[4,5-c]- quinolin-1-yl)benzonitrile MS: 429.1 (M +H⁺), TLC (HPTLC): R_(f) = 0.22 (ethyl acetate/ethanol 5:1, parts byvolume) 0.1-0.5 39

3-Fluoro-4-[7-methoxy-3-methyl- 2-oxo-8-(2H-pyrazol-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1- yl]benzonitrile MS: 415.1 (M + H⁺), TLC(HPTLC): R_(f) = 0.30 (ethyl acetate/ethanol 8:1, parts by volume) <0.140

3-Fluoro-4-[7-methoxy-3-methyl- 8-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-2-oxo-2,3-dihydro- imidazo[4,5-c]quinolin-1-yl]-benzonitrile MS: 497.1 (M + H⁺), TLC (HPTLC): R_(f) = 0.33 (ethylacetate/ethanol 5:1, parts by volume) 0.1-0.5 41

3-Fluoro-4-[7-methoxy-3-methyl- 2-oxo-8-((E)-2-thiophen-3-yl-viniyl)-2,3-dihydroimidazo- [4,5-c]quinolin-1-yl]benzonitrile MS: 457.1(M + H⁺), TLC (HPTLC): R_(f) = 0.47 (ethyl acetate/ethanol 2:1, parts byvolume) <0.1 42

3-Fluoro-4-[7-methoxy-3-methyl- 2-oxo-8-(2-thiophen-3-ylethyl)-2,3-dihydroimidazo[4,5-c]- quinolin-1-yl]benzonitrile MS: 458.8 (M +H⁺), TLC (HPTLC): R_(f) = 0.56 (ethyl acetate/ethanol 2:1, parts byvolume) 0.1-0.5 43

3-Fluoro-4-[7-methoxy-3- methyl-2-oxo-8-((E)-styryl)-2,3-dihydroimidazo[4,5-c]quinolin- 1-yl]benzonitrile MS: 451.1 (M + H⁺), TLC(HPTLC): R_(f) = 0.46 (ethyl acetate/ethanol 2:1, parts by volume)0.1-0.5

EXAMPLE 5 DNA-PK/Biochemical Assay

The kinase assay was carried out in streptavidin-coated 348-wellmicrotitre FlashPlates®. To this end, 1.5 μg of the DNA-PK/proteincomplex and 100 ng of biotinylated substrate, such as, for example,PESQEAFADLWKK biotin-NH2 (“biotin-DNA-PK peptide”), in a total volume of36.5 μl (34.25 mM HEPES/KOH, 7.85 mM Tris-HCl, 68.5 mM KCl, 5 μM ATP,6.85 mM MgCl₂, 0.5 mM EDTA, 0.14 mM EGTA, 0.69 mM DTT, pH 7.4), wereincubated at room temperature for 90 min with 500 ng of DNA from calfthymus, 0.1 μCi of 33P-ATP and 1.8% of DMSO per well with or without thetest compound. The reaction was stopped using 50 μl/well of 200 mM EDTA.After incubation for a further 30 min at room temperature, the liquidwas removed. Each well was washed three times with 100 μl of 0.9% sodiumchloride solution. A non-specific reaction (blank value) was determinedusing 10 μM of a proprietary kinase inhibitor. The radioactivitymeasurement was carried out by means of a TopCount. IC₅₀ values werecalculated in RS1 (Kashishian et al. (2003) Molecular CancerTherapeutics 1257).

EXAMPLE 6 Cellular DNA-PK Phosphorylation at Serine 2056

HCT116 cells were cultivated in MEM alpha medium with 10% of foetal calfserum, 1 mM sodium pyruvate and 2 mM glutamine at 37° C. and 10% CO₂.The cells were detached from the base of the culture vessels with theaid of trypsine/EDTA, centrifuged off in centrifuge tubes and taken upin fresh medium. The cell density was subsequently determined. 200,000cells were sown per cavity of a 12-well cell culture plate in 1 ml ofculture medium and cultivated overnight. Next day, 10 μM bleomycin andtest substances in fresh culture medium was added to the cells and thesewere cultivated for a further six hours. Cell lysis was subsequentlycarried out. The cell lysates were investigated by SDS polyacrylamidegel electrophoresis by means of DNA-PK-specific antibodies (Abcamab13852: total DNA-PK; ab18192: phosphoserine 2056 DNA-PK) and WesternBlotting. The enzymatic reaction was developed with the aid of achemiluminescence reagent. The chemiluminescence was recorded with theaid of a documentation system (VersaDoc™, Bio-Rad, USA) and evaluateddensitometrically with the aid of instrument-specific software (QuantityOne). The signals with phospho-DNA-PK-specific antibodies werestandardised to the signal with the antibody against the total proteinDNA-PK. IC₅₀ values and percentage inhibition data were determined byreferencing to the signal level of the bleomycin-treated vehicle controlgroup.

EXAMPLE 7 Cellular Colony Growth Test

The colorectal carcinoma cell line HCT116 was cultivated in MEM alphamedium with 10% oif foetal calf serum, 1 mM sodium pyruvate and 2 mMglutamine at 37° C. and 10% CO₂. The cells were detached from the baseof the culture vessels with the aid of trypsine/EDTA, centrifuged off incentrifuge tubes and taken up in fresh medium. The cell density wassubsequently determined. 300 cells were sown out in 6-well cell cultureplates in 2 ml of culture medium and cultivated overnight. Next day, thecells were treated with test substances for one hour before the cellculture plates were treated with defined doses of X-rays (in general 0,2.4, 4.8, 12 Gray; irradiation instrument: Faxitron RX-650; FaxitronX-Ray LLC, USA). In order to determine the dose/effect relationships,the cells were treated with various concentrations of a test substance.After irradiation, the cells are cultivated for a further 24 hours inthe presence of the test substance, the culture medium was then replacedwith culture medium without test substance, and the cells werecultivated for a further 6-8 days. The cell colonies formed weresubsequently stained with the aid of Crystal Violet and counted in acolony counter (Gelcount, Oxford Optronics, UK). Dose/effect curves, inparticular IC₅₀ values, were determined using a curve adaptationfunction for nonlinear dose/effect relationships.

EXAMPLE 8 Cellular CHK2 Phosphorylation at Threonine 68

HCT116 cells were cultivated in MEM alpha medium with 10% of foetal calfserum, 1 mM sodium pyruvate and 2 mM glutamine at 37° C. and 10% CO2.The cells were detached from the base of the culture vessels with theaid of trypsine/EDTA, centrifuged off in centrifuge tubes and taken upin fresh medium. The cell density was subsequently determined. 50,000cells were sown per cavity of a 96-well cell culture plate in 0.1 ml ofculture medium and cultivated overnight. Next day, 10 μM bleomycin andtest substances in fresh culture medium were added to the cells andthese were cultivated for a further six hours. After lysis of the cells,phospho-threonine 68 of the CHK2 kinase was detected in the lysates withthe aid of a phospho-CHK2 (Thr68)-specific ELISA detection system(Catalogue No. 7037, Cell Signaling Technologies, USA). The ELISA colourreaction was measured spectrophotometrically at 450 nm. The extinctionof the unstimulated controls (vehicle control without bleomycin) wassubtracted from the extinction values of the treatment groups. Thecontrols which were treated with bleomycin were set equal to 100% andall other extinction values were set in relation thereto. IC₅₀ valueswere determined with the aid of the GraphPad Prism statistics program(GraphPad Software, USA) or Assay Explorer (Symyx Technologies Inc.,USA).

EXAMPLE 9 Pharmaceutical Compositions EXAMPLE A Injection Vials

A solution of 100 g of active compound according to the invention and 5g of disodium hydrogenphosphate in 3 l of bidistilled water was adjustedto pH 6.8 using 2 N hydrochloric acid, sterile-filtered, transferredinto injection vials, lyophilised under sterile conditions and sealedunder sterile conditions. Each injection vial contained 5 mg of activecompound according to the invention.

EXAMPLE B Suppositories

A mixture of 20 g of active compound according to the invention with 100g of soya lecithin and 1400 g of cocoa butter was melted, poured intomoulds and allowed to cool. Each suppository contained 20 mg of activecompound according to the invention.

EXAMPLE C Solution

A solution was prepared from 1 g of active compound according to theinvention, 9.38 g of NaH₂PO₄*2 H₂O, 28.48 g of Na₂HPO₄*12 H₂O and 0.1 gof benzalkonium chloride in 940 ml of bidistilled water. The pH wasadjusted to 6.8, and the solution was made up to 1 l and sterilised byirradiation. This solution could be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of active compound according to the invention were mixed with99.5 g of Vaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active compound according to the invention, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate was pressed in a conventional manner to give tablets in such away that each tablet contained 10 mg of active compound according to theinvention.

EXAMPLE F Dragees

Tablets were pressed analogously to Example E and then coated in aconventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active compound according to the invention were introduced intohard gelatine capsules in a conventional manner in such a way that eachcapsule contained 20 mg of active compound according to the invention.

EXAMPLE H Ampoules

A solution of 1 kg of active compound according to the invention in 60 lof bidistilled water was sterile-filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contained 10 mg of active compound according tothe invention.

EXAMPLE I Inhalation Spray

14 g of active compound according to the invention were dissolved in 10;of isotonic NaCl solution, and the solution was transferred intostandard commercial spray vessels with pump mechanism. The solutioncould be sprayed into mouth or nose. One spray shot (approx. 0.1 ml)corresponded to a dose of approx. 0.14 mg.

1. Compounds of the formula (I)

in which R1 denotes Y or —(CY₂)_(n)—Ar, R2 denotes Y,—(CY₂)_(p)—(C[YR6])_(s)—R7 or -alk-R7, R3 denotes Y or CN, R4 denotes Y,Hal, —(CY₂)_(p)—COOY or —(CY₂)_(p)—CO—NYY, R5 denotes A, Hal,—(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, —(CY₂)—COOY, —(CY₂)_(p)—CO—NYY or—(CY₂)_(p)—NY—COY, R6 denotes Y, Hal, —(CY₂)_(n)—NYY,—(CY₂)_(n)—NY—COO—(CY₂)—SiA₃, —(CY₂)_(n)—COOY, —CO—NYY, —CO—NY—(CY₂)—OY,—CO—NY—(CY₂)_(n)—NYY or SO₂A, R7 denotes —(CY₂)_(p)—Ar or—(CY₂)_(p)-Het¹, X denotes CH₂, O, S or a single bond, Y denotes H or A,A denotes unbranched or branched alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9or 10 C atoms, where 1, 2, 3, 4, 5, 6 or 7 H atoms may be replaced,independently of one another, by Hal, Alk denotes alkenyl having 1, 2,3, 4, 5 or 6 C atoms, where 1, 2, 3 or 4 H atoms may be replaced,independently of one another, by Hal and/or OY, Ar denotes phenyl whichis unsubstituted or mono-, di- or trisubstituted by Hal, A, CN,—(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY or—(CY₂)_(p)—NY—COY, Het¹ denotes mono- or bicyclic heteroaryl having 2,3, 4, 5, 6, 7, 8 or 9 C atoms and 1, 2, 3 or 4 N, O and/or S atoms,which may be unsubstituted or mono-, di- or trisubstituted by Hal, A,CN, —(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY,—(CY₂)_(p)—NY—COY or —SO₂—Het², Het² denotes a monocyclic saturatedheterocycle having 2, 3, 4, 5, 6 or 7 C atoms and 1, 2, 3 or 4 N, Oand/or S atoms, which may be unsubstituted or monosubstituted by A, Haldenotes F, Cl, Br or I, m denotes 0, 1, 2, 3 or 4, and n, p, s,independently of one another, denote 0, 1, 2, 3, 4, 5 or 6, in the formof pharmaceutically usable derivatives, hydrates, solvates or precursorsthereof, including mixtures thereof in all ratios.
 2. The derivatives,hydrates, solvates or precursors of the compounds according to claim 1having the sub-formula (IA)

in which R2 denotes Y or —(CY₂)_(p)—C(YR6)-R7, R5 denotes Y or Hal, R6denotes Y, —(CY₂)_(n)—NYY, —CO—NYY or —CO—NY—(CY₂)_(n)—OY, R7 denotes Aror Het¹, Y denotes H or A, A denotes unbranched or branched alkyl having1, 2, 3 or 4 C atoms, where 1, 2 or 3 H atoms may be replaced,independently of one another, by Hal, Ar denotes phenyl which isunsubstituted or mono- or disubstituted by Hal, Het¹ denotes mono- orbicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8 or 9 C atoms and 1, 2 or3 N and/or S atoms, which may be unsubstituted or mono- or disubstitutedby Hal, A, OY or —SO₂—Het², Het² denotes a monocyclic saturatedheterocycle having 3, 4 or 5 C atoms and 1 or 2 N and/or O atoms, Haldenotes F, Cl, Br or I, and n, p, independently of one another, denote0, 1, 2 or 3, and/or physiologically acceptable salts, tautomers and/orstereoisomers thereof, including mixtures thereof in all ratios.
 3. Thederivatives, hydrates, solvates or precursors of the compounds accordingto claim 1 having the sub-formula (IB)

in which R2 denotes R7, -alk-Ar or -alk-Het¹, R5 denotes Y or Hal, R7denotes —(CY₂)_(p)—Ar or —(CY₂)_(p)-Het¹, Y denotes H or A, A denotesunbranched or branched alkyl having 1, 2, 3 or 4 C atoms, where 1, 2 or3 H atoms may be replaced, independently of one another, by Hal, Alkdenotes alkenyl having 1, 2 or 3 C atoms, where 1 or 2 H atoms may bereplaced by Hal and/or OH, Ar denotes phenyl which is unsubstituted ormono- or disubstituted by Hal, Het¹ denotes mono- or bicyclic heteroarylhaving 2, 3, 4, 5, 6, 7, 8 or 9 C atoms and 1, 2 or 3 N and/or S atoms,which may be unsubstituted or mono- or disubstituted by Hal, A, OY or—SO₂—Het², Het² denotes a monocyclic saturated heterocycle having 3, 4or 5 C atoms and 1 or 2 N and/or O atoms, Hal denotes F, Cl, Br or I,and p denotes 0, 1, 2 or 3, and/or physiologically acceptable salts,tautomers and/or stereoisomers thereof, including mixtures thereof inall ratios.
 4. The derivatives, hydrates, solvates or precursors of thecompounds according to claim 3 having the sub-formula (IB-1)

in which R2 denotes R7, -alk-Ar or -alk-Het¹, R5 denotes Hal, R7 denotesAr or Het¹, A denotes unbranched or branched alkyl having 1, 2, 3 or 4 Catoms, where 1, 2 or 3 H atoms may be replaced, independently of oneanother, by Hal, Alk denotes alkenyl having 1 or 2 C atoms, Ar denotesphenyl which is unsubstituted or monosubstituted by Hal, Het¹ denotesmono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8 or 9 C atoms and1, 2 or 3 N and/or S atoms, which may be unsubstituted or mono- ordisubstituted by Hal or A or, and Hal denotes F, Cl, Br or I, and/orphysiologically acceptable salts, tautomers and/or stereoisomersthereof, including mixtures thereof in all ratios.
 5. The derivatives,hydrates, solvates or precursors of the compounds according to claim 1,of the formula:

or mixtures thereof in all ratios.
 6. (canceled)
 7. (canceled) 8.(canceled)
 9. (canceled)
 10. A method for the inhibition ofserine/threonine protein kinases in vitro comprising introducing acompound of the formula

in which R1 denotes Y or —(CY₂)_(n)—Ar R2 denotes Y,—(CY₂)_(p)—(C[YR6])_(s)-R7 or -alk-R7, R3 denotes Y or CN, R4 denotes Y,Hal, —(CY₂)_(p)—COOY or —(CY₂)_(p)—CO—NYY, R5 denotes A, Hal,—(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY or—(CY₂)_(p)—NY—COY, R6 denotes Y, Hal, —(CY₂)_(n)—NYY,—(CY₂)_(n)—NY—COO—(CY₂)_(n)—SiA₃, —(CY₂)_(n)—COOY, —CO—NYY,—CO—NY—(CY₂)_(n)—OY, —CO—NY—(CY₂)_(n)—NYY or SO₂A, R7 denotes—(CY₂)_(p)—Ar or —(CY₂)_(p)-Het¹, X denotes CH₂, O, S or a single bond,Y denotes H or A, A denotes unbranched or branched alkyl having 1, 2, 3,4, 5, 6, 7, 8, 9 or 10 C atoms, where 1, 2, 3, 4, 5, 6 or 7 H atoms maybe replaced, independently of one another, by Hal, Alk denotes alkenylhaving 1, 2, 3, 4, 5 or 6 C atoms, where 1, 2, 3 or 4 H atoms may bereplaced, independently of one another, by Hal and/or OY, Ar denotesphenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A,CN, —(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY or—(CY₂)_(p)—NY—COY, Het¹ denotes mono- or bicyclic heteroaryl having 2,3, 4, 5, 6, 7, 8 or 9 C atoms and 1, 2, 3 or 4 N, O and/or S atoms,which may be unsubstituted or mono-, di- or trisubstituted by Hal, A,CN, —(CY₂)_(p)—OY, —(CY₂)_(p)—NYY, —(CY₂)_(p)—COOY, —(CY₂)_(p)—CO—NYY,—(CY₂)_(p)—NY—COY or —SO₂—Het², Het² denotes a monocyclic saturatedheterocycle having 2, 3, 4, 5, 6 or 7 C atoms and 1, 2, 3 or 4 N, Oand/or S atoms, which may be unsubstituted or monosubstituted by A, Haldenotes F, Cl, Br or I, m denotes 0, 1, 2, 3 or 4, and n, p, s,independently of one another, denote 0, 1, 2, 3, 4, 5 or 6, and/orphysiologically acceptable salts, tautomers and/or stereoisomersthereof, including mixtures thereof in all ratios to a sample containingserine/threonine protein kinases.
 11. (canceled)
 12. (canceled) 13.(canceled)
 14. (canceled)
 15. (canceled)